Range of Purposes Behind Codes
Codes of ethics in the professions serve numerous purposes. At the level of the profession itself, codes document the standards according to which the profession can be held accountable for the conduct of its members. Further, because society relegates control for many of the professions to the professional organizations themselves, the professions have developed codes to provide the basis of self-regulation (Soskolne 1989). At the level of the individual professional, codes can provide a practical guide to members of the profession who might be experiencing a moral or ethical dilemma concerning their professional conduct in a particular circumstance. Where a professional finds himself or herself in a state of moral or ethical tension, it is self-evident that codes can be helpful in providing counsel.
The existence of a code provides the basis of a profession’s ethics programme of activity designed to instil ethical standards among its membership (Gellermann, Frankel and Ladenson 1990; Hall 1993). Revisions to the code can be considered through grass-roots individual membership input at organizational meetings, workshops and conferences. This ongoing discussion of issues and concerns constitutes a review process ensuring that any code remains sensitive to changing social values. Professions depending for their sustenance on public support thereby improve their likelihood of remaining publicly accountable and relevant (Glick and Shamoo 1993).
Codes could assist professionals being charged with malpractice and perhaps even in litigation. Demonstrated adherence to one’s professional code would likely be deemed indicative of adherence to standards of practice consistent with professional norms. If such practice were to have resulted in harm, the code-abiding individual professional would be less likely to be found guilty of having committed a wrong. However, based on the principle of trust (Pellegrino, Veatch and Langan 1991), the public has the expectation that the best possible professional judgement will be exercised in the public interest. Where the physician-patient relationship is concerned, the patient has the right under the principle of trust to expect that his or her interests will be best served. However, an ethical tension arises when the public good is potentially harmed in circumstances where the individual patient’s best interests are being served. In such circumstances, it is the public good that will usually need to take precedence over that of the individual. Regardless, codes provide no substitute for legal liability dimensions of conduct for which government has enacted laws to protect the public interest (Cohen 1982).
Weight and Intent of Codes
Codes do have associated with them the notion of statutory force, implying the ability for their enforcement through the administering of some type of disciplinary action. Indeed, the notions of accountability and self-regulation referred to above have associated with them some sense of control (minimally, peer pressure; maximally, the removal of licence to practice) that can be exercised over the members of the profession by the professional organization itself. Because of this, some professional organizations have preferred to avoid these connotations associated with codes and opt rather for “guidelines”. The latter emphasize guidance with fewer implications for enforcement associated with them. Other groups have preferred to avoid all connotations associated with codes or guidelines; instead, they have preferred to develop “declarations on ethics” for their specific organizations (Jowell 1986). Throughout this chapter the term code will imply “guidelines”.
It should be apparent that codes (and also guidelines) do not carry the force of law. In essence, codes and guidelines are intended to provide guidance for professionals, collectively and individually, in their relationships with their clients (including patients and research subjects), with their colleagues and co-workers (including their students), and with the public (including stakeholder groups). In addition, codes require that the quality of professional work and hence the stature of the profession itself is advanced. In general, codes associated with the physician-patient relationship will require that the patient’s interests take precedence over any other interests; the physician is placed firmly in the position of “patient advocate”. One exception to this would arise in the context of infectious diseases, where the patient’s rights may have to be considered second to the public welfare. In contrast, however, it can generally be stated that codes associated with scientific research will require that the public interest take precedence over any individual or other interests. One exception would be where a researcher discovers child abuse in a research subject; here the researcher would have the obligation to report this to the child welfare authorities.
Code Development, Review and Revision
The process by which codes are developed has consequences for their application. By including members of the profession and students of the profession in code development, as well as in code review and revision, ownership of the resultant document by a greater number of individuals is believed more likely. With broad-based ownership, increased compliance by a greater number is believed more assured.
Content and Structure of Codes
The content of a code should be user friendly to maximize its utility. Codes can be of varying length. Some are brief, while some are substantial. The more substantial that a code is, the more specific it is possible for it to be. Codes can be made to be user friendly by virtue of their structure and content. For example, a summary set of the principles upon which the code is based could be presented first, followed by expanded aspirational or prescriptive statements, which constitute the code itself. These can be followed by a commentary that explicates each statement in turn, perhaps noting special circumstances in the form of case studies that might serve as useful examples. The principles and their interpretation(s), however, are highly dependent on the values recognized as inherent to the pursuits of a profession. While these values may be universal, interpretations as well as practices at the local and regional levels may differ. Thus, while a statement of the profession’s core values can provide an anchor for its statements on ethics and should appear as a preface to the guidelines (Gellermann, Frankel and Ladenson 1990), sensitivity to regional differences can be demonstrated through the more detailed commentary and case study materials.
The commentary should incorporate, or could be followed by or complemented with, case study materials that derive from real-life instances of ethical dilemmas or tensions. The case study materials could be ethically analysed in either sanitized (i.e., anonymous) form, or can be made to reflect the parties involved (of course, only with the approval of the parties for their names to be included) (for example, Soskolne 1991). The objective behind case studies is not to seek retribution, but rather to provide examples for teaching purposes. Learning is enhanced by real-life situations.
It is from an understanding of the code that it becomes possible for a profession to develop more detailed standards of practice. These address more specific areas of activity associated with professional conduct, including a broad range of activity from interpersonal behaviours to both how research is conducted and how the results of that research are communicated. Standards of practice for the profession could be included in an ethics package; they reflect on each profession’s skill set and therefore add particular considerations that go beyond the statement of its ethics principles.
Scope of Codes
The development of a code by any profession has almost invariably tended to be driven by issues having a direct bearing on that profession. Consequently, codes tend to have a focus narrowly defined by each profession’s own concerns. However, codes also need to take broader social issues into account (Fawcett 1993). In fact, in a recent analysis of several codes, Summers et al. (1995) found that guidelines on specific social issues, such as environmental effects or conflict resolution, are scarcely mentioned at all in existing codes. Because the professions manifest substantial influence, if their codes indeed were to take broader social issues into account, then a great confluence and concurrence of effort would be brought to bear on those areas of human endeavour that currently fall between the cracks in promoting the common social good. Such pressure could help reduce dangers to human welfare, such as militarism and ecological destruction.
Ethics Training
It should be recognized that there exist two schools of thought for ethics training: one is based in a principle-driven approach while the other is case based, also known as casuistry. It is this author’s view, which remains to be tested, that a balance between the two is essential for successful applied ethics training in the professions (Soskolne 1991/92). However, it is well known that ethically analyzed case study material has an invaluable role to play in the education process. Cases provide a context for applying principles.
Because graduate ethics training in the professions is becoming more recognized as an essential place for students to gain awareness of the values, ethical principles and standards of practice of the profession, a model curriculum might ideally be included as part of a code; this will facilitate the training of students intent on entering the profession. The need for this is demonstrated through a recent survey that identified inconsistencies and shortcomings regarding the ethics components in graduate training programmes across the United States (Swazey, Anderson and Seashore 1993).
Recent History of Codes in Selected Professions
In western cultures, the medical profession has had the advantage of discussions about ethics since the time of Socrates (470–399 B.C.), Plato (427–347 B.C.) and Aristotle (384–322 B.C.) (Johnson 1965). Since then, codes have been developed and periodically revised in response to newly recognized issues arising, for example, from human value shifts and, more recently, from technological advances (Declaration of Helsinki 1975; Ad hoc Committee on Medical Ethics 1984; Russel and Westrin 1992). Since the 1960s, other professions have become involved in code development for their own professional organizations. The area of professional codes in fact has become a cottage industry since the 1980s. The American Association for the Advancement of Science (AAAS) has been instrumental in this movement. Under the auspices of its Committee on Scientific Freedom and Responsibility, AAAS initiated a seminal professional ethics project designed to examine the features of and activities associated with codes in the science and engineering professions. The report arising from this effort subsequently generated renewed interest in discussing both code development and revision with many of the professions (Chalk, Frankel and Chafer 1980).
The health/caring professions have long been engaged in discussions of ethical tensions arising from the nature of their professional pursuits. The codes that have evolved have tended, however, to focus on the physician-patient relationship, with concerns about confidentiality being pre-eminent. More recently, perhaps motivated by the growth of applied health research, codes have expanded their attention to include issues pertaining to researcher-patient relationships. Because of population-based research, codes now are addressing concerns for researcher-population relationships. The latter has been aided by the experience of other professions such as sociology, anthropology and statistics.
Many of the caring professions related to the practice of occupational health have been engaged in the discussion of professional ethics. These include: industrial hygiene (Yoder 1982; LaDou 1986); epidemiology (Beauchamp et al. 1991; IEA Workshop on Ethics, Health Policy and Epidemiology 1990; Chemical Manufacturers Association’s Epidemiology Task Group 1991; Council for International Organizations of Medical Sciences 1991, 1993); medicine and numerous of its subspeciality areas, including occupational medicine (Coye 1982; American Occupational Medical Association 1986; International Commission on Occupational Health 1992; Standing Committee of Doctors of the EEC 1980); nursing; toxicology; statistics (International Statistical Institute 1986); psychology; engineering and risk analysis.
In the occupationally specific areas of health services (Guidotti et al. 1989), medicine (Samuels 1992) and health and safety (LaDou 1986), as well as in occupational and environmental health (Rest 1995), relevant portions of professional codes have been abstracted. These presentations serve well the need for furthering discussion in these areas with a view to revising extant codes.
The importance of integrating ethics into the day-to-day activities of professionals is exemplified by these recent texts, which contain appropriately detailed sections on ethics. The professional thereby is reminded that in all aspects of professional practice, all decisions and recommendations have consequences with associated ethical underpinnings.
More recent work on the subject of misconduct in science requires integration into newer texts (Dale 1993; Grandjean and Andersen 1993; Office of the Assistant Secretary for Health 1992; Price 1993; Reed 1989; Sharphorn 1993; Soskolne 1993a; Soskolne 1993b; Soskolne and Macfarlane, 1995; Teich and Frankel 1992). Because one of the fundamental goals of science is the pursuit of truth through objectivity, plagiarism and the fabrication or the falsification of data are counter to the scientific ethic. As the scientific enterprise expands to include more and more scientists, misconduct in science is coming to the attention of the public more frequently. However, it is believed that even in the face of increasing competition and the potential for conflicting interests, the vast majority of those engaged in science do adhere to the principles of truth and objectivity. The frequency of misconduct does, however, remain difficult to assess (Goldberg and Greenberg 1993; Greenberg and Martell 1992; Frankel 1992).
The potential harm to particular scientific efforts as a result of misconduct is one concern. Another concern is the loss of faith by the public in scientists, with consequent reductions in support for the scientific enterprise. The latter has such potentially dire consequences for both science and society that all scientists, and especially students of science, need to be trained in the scientific ethic and reminded of these principles from time to time.
Several case studies serve to demonstrate misconduct (Broad and Wade 1982; Office of Research Integrity 1993; Price 1993; Needleman, Geiger and Frank 1985; Soskolne and Macfarlane, 1995; Swazey, Anderson and Seashore 1993; Soskolne 1991). The determinants of ethical dilemmas are numerous, but one survey among risk analysts in New Jersey (Goldberg and Greenberg 1993) suggests that the two most important causes are “on the job pressure” and “pressure caused by economic implications of result”. The authors of this study noted that possible causes of misconduct include “conflicts of interest, competition with unregulated and unscrupulous competitors, and general lack of individual or societal ethics”. While some codes do address the need for honesty and objectivity in science, the seriousness of current pressures to perform in the presence of apparently declining awareness of societal ethics would dictate that training at all levels include the subject of ethics, values and philosophy. Indeed, the United States Public Health Service requires that universities seeking to obtain research grant support have procedures in place for dealing with and reporting misconduct in science (Reed 1989). Furthermore, university training programmes in public health disciplines must include ethics teaching to qualify for federal funding (Office of the Assistant Secretary for Health 1992).
Normative Nature of Codes
Codes of professional conduct tend to be a narrative description of an assemblage of normative practices. These practices pertain to the moral and ethical standards of a group, be it a professional organization, association or society, having a common skill set in the service of people.
The basis of respective codes has been the so-called Golden Rule, which prescribes that one should do to others what one would have others do to oneself, do one’s level best, and call to the attention of others any act of misconduct.
Approaches to Developing Codes
Most professional organizations have produced codes through the top-down approach, where the elected officials of the profession have undertaken the task. However, as noted earlier (see “Code development, review and revision”), the bottom-up approach is more likely to result in compliance with codes, because grass-roots participation in the process results in a feeling of ownership of the outcome and hence a greater likelihood of compliance. The view that the power brokers of the profession have major influence over the specification of what constitutes appropriate professional conduct could detract from the credibility associated with any resultant code. The more that the “final” code is reflective of community norms, the greater the likelihood that it will be adhered to.
Codes developed by international organizations do have the power of influencing regional groups of people to consider the concerns and statements included in international codes. In this way, regions that have not given attention to the development of codes might be stimulated to do so. Presumably, provided the intent of international codes is limited to a function of providing stimulus, ongoing interaction could serve to iteratively modify and update international codes so that ultimately the international code could well reflect transnational concerns. Care must be exercised to respect regional cultural norms that are not in conflict with, for example, accepted declarations on human rights. Hence, code makers should be sensitive to cultural differences, and not allow their work to homogenize human behaviour; cultural diversity must rather be encouraged.
Mechanisms for Enforcement
Noted earlier was the fact that codes do imply some degree of self-regulation if the expectation of accountability is to have meaning. This would suggest the existence of procedures for investigating allegations of misconduct (or malpractice) of any type, and for correcting conduct deemed professionally inappropriate (Price 1993; Dale 1993; Grandjean and Andersen 1993). In addition, some remedy might be provided for any harms that might have derived from professional misconduct.
The procedures to be invoked in investigations of allegations of misconduct or malpractice must be pre-specified. The maxim of “innocent until proven guilty” should be evident and be seen to be applied. However, because public confidence rests on professional self-regulation, investigations should be dealt with as efficiently as possible with respect for due process at all times (Sharphorn 1993; Soskolne 1993a, b).
The threat of revoking professional licence to practice is one way that the profession has leverage to maximize among its members adherence to any codes. Many professions have no such leverage; their membership is made up of dues-paying individuals with a wide range of qualifications for which regional legislatures have not required licensure as a requirement of membership in the profession. The loss of the right to practice one’s profession therefore is not applicable in many professions as a penalty for misconduct. The only recourse in such instances is that of peer pressure.
Current Issues of Concern to Occupational Health Professionals
It is not within the scope of this article to develop a comprehensive code, but rather to present the process by which codes are developed. It is the intent in so doing to provide motivation for the ongoing discussion of codes (as a component of a broader-based professional ethics programme) and to alert the reader to current issues about which further discussion is needed for the possible inclusion of such resolved matters into revised codes.
As noted by Guidotti et al. (1989), certain issues had been overlooked in codes that existed at that time. These included the virtue of full access to accurate information, and that the burden of risk should not be taken by the worker in the presence of unproved but sound evidence. The question of accurate information and implied truth has associated with it issues of scientific integrity (as referred to in North America) or of scientific dishonesty (as referred to in Denmark) (Andersen et al. 1992; Grandjean and Andersen 1993). Clearly, the pursuit of truth as the main target of scientific endeavour must be reinforced at every opportunity, including its full integration into codes, case study materials and ethics programmes generally (Hall 1993).
With technological advances, the ability grows to more precisely measure biological parameters. For example, biomarkers is one area that opens up a Pandora’s box of ethical issues and resulting tensions that have yet to be addressed in codes. Several such issues have been identified by Ashford (1986) and by Grandjean (1991). Since existing codes were developed prior to the availability on a commercial scale of this technology, codes would serve the occupational health community better if they were updated to provide some guidance on related concerns. To achieve this, explication of such thorny questions as the workers’ right to work in the face of high-risk susceptibility identified through biomarker assays, requires extensive discussion in workshops and conferences specially convened for the purpose. Case study materials would assist in this effort. So profound are the ramifications of biomarker studies that their implications, as well as those related to other potential high technology breakthroughs, could be best addressed through the profession’s continual review of the code.
Because issues such as biomarkers can be difficult to resolve, it may be appropriate for like professions dealing with similar issues to consolidate their efforts and establish mechanisms for exchanging information to assist in the resolution of difficult and challenging related ethical issues. In particular, the need to address the timing for introducing high technology procedures for which ethical considerations have not yet been established also needs to be recognized and addressed by standing committees on ethics for the respective occupational safety and health professions. Other stakeholder groups probably should be included in such deliberations, including the community representatives themselves on whom such studies would be conducted.
In a researcher’s enthusiasm to implement new technological measures into studies for which the ramifications are not fully understood (in the belief that benefit would result), it should be recognized that greater harm than benefit to the subjects of these studies could, in fact, arise (e.g., job loss today is potentially more harmful than the possibility of premature death at some future date). Hence, great caution must be exercised in advance of the implementation of such technologies. Only after due discussion has been exercised by the professional groups having an interest in the use of such technologies, together with a broad range of stakeholder interest groups, should their implementation be considered.
Another current issue involves the notion of data privacy, which is one that returns to the public arena periodically. In the age of computers, the potential exists for linking records created for one purpose with records created for another purpose. Advocates of data privacy have been concerned that records so created could be potentially damaging to individuals. While individual rights to privacy must take precedence over the research needs of the community, the fact that population-based research is uninterested in the data at the individual level must be brought to the attention of the data privacy advocates. In so doing, it should be easy to demonstrate that the public good is better served by allowing appropriately qualified researchers, trained in data processing and confidentiality, access to individual data for population-based research purposes.
Concern about the extension of principlism applied in the physician-patient setting to that of the community-research situation has been noted above (see “Recent history of codes in selected professions”). Vineis and Soskolne (1993) have found that the established principles of autonomy, beneficence, non-maleficence and distributive justice are not easily applicable at the societal level. For example, available information about the safety of exposures often is too scanty to allow decisional autonomy; beneficence is considered from the societal viewpoint rather than from that of the individual; and equity is frequently violated. Ethics require careful consideration when defining what is acceptable to society; the simple mathematical formulations used for risk-benefit evaluations cannot be applied directly to individuals. Further development and integration of these ideas are necessary.
In conclusion, codes have a fundamental role to play in the professions. They also could play an important role in safeguarding the common good if they took broader social issues into account. They need to be developed with grass-roots and stakeholder input as part of a broad-based programme of ethics supported by each profession. Codes—including the profession’s core values, the commentary associated with a code and case study materials—must be subjected to a process of periodic review and revision. Now, more than ever, codes are needed not only for professional accountability and self-regulation purposes, but also to help practitioners with the moral and ethical challenges faced by constantly advancing technologies that have implications, amongst others, for the rights and duties of all affected individuals and interest groups. A substantial and challenging task lies ahead.
Lung function may be measured in a number of ways. However, the aim of the measurements has to be clear before the examination, in order to interpret the results correctly. In this article we will discuss lung function examination with special regard to the occupational field. It is important to remember the limitations in different lung function measurements. Acute temporary lung function effects may not be discernible in case of exposure to fibrogenic dust like quartz and asbestos, but chronic effects on lung function after long-term (>20 years) exposure may be. This is due to the fact that chronic effects occur years after the dust is inhaled and deposited in the lungs. On the other hand, acute temporary effects of organic and inorganic dust, as well as mould, welding fumes and motor exhaust, are well suited to study. This is due to the fact that the irritative effect of these dusts will occur after a few hours of exposure. Acute or chronic lung function effects also may be discernible in cases of exposure to concentrations of irritating gases (nitrogen dioxide, aldehydes, acids and acid chlorides) in the vicinity of well documented exposure limit values, especially if the effect is potentiated by particulate air contamination.
Lung function measurements have to be safe for the examined subjects, and the lung function equipment has to be safe for the examiner. A summary of the specific requirements for different kinds of lung function equipment are available (e.g., Quanjer et al. 1993). Of course, the equipment must be calibrated according to independent standards. This may be difficult to achieve, especially when computerized equipment is being used. The result of the lung function test is dependent on both the subject and the examiner. To provide satisfactory results from the examination, technicians have to be well trained, and able to instruct the subject carefully and also encourage the subject to carry out the test properly. The examiner should also have knowledge about the airways and lungs in order to interpret the results from the recordings correctly.
It is recommended that the methods used have a fairly high reproducibility both between and within subjects. Reproducibility may be measured as the coefficient of variation, that is, the standard deviation multiplied by 100 divided by the mean value. Values below 10% in repeated measurements on the same subject are deemed acceptable.
In order to determine if the measured values are pathological or not, they must be compared with prediction equations. Usually the prediction equations for spirometric variables are based on age and height, stratified for sex. Men have on the average higher lung function values than women, of the same age and height. Lung function decreases with age and increases with height. A tall subject will therefore have higher lung volume than a short subject of the same age. The outcome from prediction equations may differ considerably between different reference populations. The variation in age and height in the reference population will also influence the predicted values. This means, for example, that a prediction equation must not be used if age and/or height for the examined subject are outside the ranges for the population that is the basis for the prediction equation.
Smoking will also diminish lung function, and the effect may be potentiated in subjects who are occupationally exposed to irritating agents. Lung function used to be considered as not being pathological if the obtained values are within 80% of the predicted value, derived from a prediction equation.
Measurements
Lung function measurements are carried out to judge the condition of the lungs. Measurements may either concern single or multiple measured lung volumes, or the dynamic properties in the airways and lungs. The latter is usually determined through effort-dependent manoeuvres. The conditions in the lungs may also be examined with regard to their physiological function, that is, diffusion capacity, airway resistance and compliance (see below).
Measurements concerning ventilatory capacity are obtained by spirometry. The breathing manoeuvre is usually performed as a maximal inspiration followed by a maximal expiration, vital capacity (VC, measured in litres). At least three technically satisfactory recordings (i.e., full inspiration and expiration effort and no observed leaks) should be done, and the highest value reported. The volume may be directly measured by a water-sealed or a low-resistive bell, or indirectly measured by pneumotachography (i.e., integration of a flow signal over time). It is important here to note that all measured lung volumes should be expressed in BTPS, that is, body temperature and ambient pressure saturated with water vapour.
Forced expired vital capacity (FVC, in litres) is defined as a VC measurement performed with a maximally forced expiratory effort. Due to the simplicity of the test and the relatively inexpensive equipment, the forced expirogram has become a useful test in the monitoring of lung function. However, this has resulted in many poor recordings, of which the practical value is debatable. In order to carry out satisfactory recordings, the updated guideline for the collection and use of the forced expirogram, published by the American Thoracic Society in 1987, may be useful.
Instantaneous flows may be measured on flow-volume or flow-time curves, while time average flows or times are derived from the spirogram. Associated variables which can be calculated from the forced expirogram are forced expired volume in one second (FEV1, in litres per second), in percentage of FVC (FEV1%), peak flow (PEF, l/s), maximal flows at 50% and 75% of forced vital capacity (MEF50 and MEF25, respectively). An illustration of the derivation of FEV1 from the forced expirogram is outlined in figure 1. In healthy subjects, maximal flow rates at large lung volumes (i.e., at the beginning of expiration) reflect mainly the flow characteristics of the large airways while those at small lung volumes (i.e., the end of expiration) are usually held to reflect the characteristics of the small airways, figure 2. In the latter the flow is laminar, while in the large airways it may be turbulent.
Figure 1. Forced expiratory spirogram showing the derivation of FEV1 and FVC according to the extrapolation principle.
Figure 2. Flow-volume curve showing the derivation of peak expiratory flow (PEF), maximal flows at 50% and 75% of forced vital capacity (and
, respectively).
PEF may also be measured by a small portable device such as the one developed by Wright in 1959. An advantage with this equipment is that the subject may carry out serial measurements—for example, at the workplace. To get useful recordings, however, it is necessary to instruct the subjects well. Moreover, one should keep in mind that measurements of PEF with, for example, a Wright meter and those measured by conventional spirometry should not be compared due to the different blow techniques.
The spirometric variables VC, FVC and FEV1 show a reasonable variation between individuals where age, height and sex usually explain 60 to 70% of the variation. Restrictive lung function disorders will result in lower values for VC, FVC and FEV1. Measurements of flows during expiration show a great individual variation, since the measured flows are both effort and time dependent. This means, for example, that a subject will have extremely high flow in case of diminished lung volume. On the other hand, the flow may be extremely low in case of very high lung volume. However, the flow is usually decreased in case of a chronic obstructive disease (e.g., asthma, chronic bronchitis).
Figure 3. A principal outline of the equipment for determination of total lung capacity (TLC) according to the helium dilution technique.
The proportion of residual volume (RV), that is, the volume of air which still is in the lungs after a maximal expiration, can be determined by gas dilution or by body plethysmography. The gas dilution technique requires less complicated equipment and is therefore more convenient to use in studies carried out at the workplace. In figure 3, the principle for the gas dilution technique has been outlined. The technique is based on dilution of an indicator gas in a rebreathing circuit. The indicator gas must be sparingly soluble in biological tissues so that it is not taken up by the tissues and blood in the lung. Hydrogen was initially used, but because of its ability to form explosive mixtures with air it was replaced by helium, which is easily detected by means of the thermal conductivity principle.
The subject and the apparatus form a closed system, and the initial concentration of the gas is thus reduced when it is diluted into the gas volume in the lungs. After equilibration, the concentration of indicator gas is the same in the lungs as in the apparatus, and functional residual capacity (FRC) can be calculated by means of a simple dilution equation. The volume of the spirometer (including the addition of the gas mixture into the spirometer) is denoted by VS, VL is the volume of the lung, Fi is the initial gas concentration and Ff is the final concentration.
FRC = VL = [(VS · Fi) / Ff] – VS
Two to three VC manoeuvres are carried out to provide a reliable base for the calculation of TLC (in litres). The subdivisions of the different lung volumes are outlined in figure 4.
Figure 4. Spirogram labelled to show the subdivisions of the total capacity.
Due to change in the elastic properties of the airways, RV and FRC increase with age. In chronic obstructive diseases, increased values of RV and FRC are usually observed, while VC is decreased. However, in subjects with badly ventilated lung areas—for example, subjects with emphysema—the gas dilution technique may underestimate RV, FRC and also TLC. This is due to the fact that the indicator gas will not communicate with closed-off airways, and therefore the decrease in the indicator gas concentration will give erroneously small values.
Figure 5. A principal outline of the recording of airway closure and the slope of the alveolar plateau (%).
Measures of airway closure and gas distribution in the lungs can be obtained in one and the same manoeuvre by the single breath wash-out technique, figure 5. The equipment consists of a spirometer connected to a bag-in-box system and a recorder for continuous measurements of nitrogen concentration. The manoeuvre is carried out by means of a maximal inspiration of pure oxygen from the bag. In the beginning of the expiration, the nitrogen concentration increases as a result of emptying the subject’s deadspace, containing pure oxygen. The expiration continues with the air from the airways and alveoli. Finally, air from the alveoli, containing 20 to 40% nitrogen, is expired. When the expiration from the basal parts of the lungs increases, the nitrogen concentration will rise abruptly in case of airway closure in dependent lung regions, figure 5. This volume above RV, at which airways close during an expiration, is usually expressed as closing volume (CV) in percentage of VC (CV%). Distribution of the inspired air in the lungs is expressed as the slope of the alveolar plateau (%N2 or phase III, %N2/l). It is obtained by taking the difference in nitrogen concentration between the point when 30% of the air is exhaled and the point for airway closure, and dividing this by the corresponding volume.
Ageing as well as chronic obstructive disorders will result in increased values for both CV% and phase III. However, not even healthy subjects have a uniform gas distribution in the lungs, resulting in slightly elevated values for phase III, that is, 1 to 2% N2/l. The variables CV% and phase III are considered to reflect the conditions in the peripheral small airways with an internal diameter about 2 mm. Normally, the peripheral airways contribute to a small part (10 to 20%) of the total airway resistance. Quite extensive changes which are not detectable by conventional lung function tests like dynamic spirometry, may occur, for example, as a result of an exposure to irritating substances in the air in the peripheral airways. This suggests that airway obstruction begins in the small airways. Results from studies also have shown alterations in CV% and phase III before any changes from the dynamic and static spirometry have occurred. These early changes may go into remission when exposure to hazardous agents has ceased.
The transfer factor of the lung (mmol/min; kPa) is an expression of the diffusion capacity of oxygen transport into the pulmonary capillaries. The transfer factor can be determined using single or multiple breath techniques; the single breath technique is considered to be most suitable in studies at the workplace. Carbon monoxide (CO) is used since the back pressure of CO is very low in the peripheral blood, in contrast to that of oxygen. The uptake of CO is assumed to follow an exponential model, and this assumption can be used to determine the transfer factor for the lung.
Determination of TLCO (transfer factor measured with CO) is carried out by means of a breathing manoeuvre including a maximal expiration, followed by a maximal inspiration of a gas mixture containing carbon monoxide, helium, oxygen and nitrogen. After a breath-holding period, a maximal exhalation is done, reflecting the content in the alveolar air, Figure 10. Helium is used for the determination of the alveolar volume (VA). Assuming that the dilution of CO is the same as for helium, the initial concentration of CO, before the diffusion has started, can be calculated. TLCO is calculated according to the equation outlined below, where k depends on the dimensions of the component terms, t is the effective time for breath-holding and log is base 10 logarithm. Inspired volume is denoted Vi and the fractions F of CO and helium are denoted by i and a for inspired and alveolar, respectively.
TLCO = k Vi (Fa,He/Fi,He) log (Fi,CO Fa,He/Fa,CO Fi,He) (t)-1
Figure 6. A principal outline of the recording of transfer factor
The size of TLCO will depend on a variety of conditions—for example, the amount of available haemoglobin, the volume of ventilated alveoli and perfused lung capillaries and their relation to each other. Values for TLCO decrease with age and increase with physical activity and increased lung volumes. Decreased TLCO will be found in both restrictive and obstructive lung disorders.
Compliance (l/kPa) is a function, inter alia, of the elastic property of the lungs. The lungs have an intrinsic tendency to collaborate—that is, to collapse. The power to keep the lungs stretched will depend on the elastic lung tissue, the surface tension in the alveoli, and the bronchial musculature. On the other hand, the chest wall tends to expand at lung volumes 1 to 2 litres above the FRC level. At higher lung volumes, power has to be applied to further expand the chest wall. At the FRC level, the corresponding tendency in the lungs is balanced by the tendency to expand. The FRC level is therefore denoted by the resting level of the lung.
The compliance of the lung is defined as the change in volume divided by the change in transpulmonary pressure, that is, the difference between the pressures in the mouth (atmospheric) and in the lung, as the result of a breathing manoeuvre. Measurements of the pressure in the lung are not easily carried out and are therefore replaced by measurements of the pressure in the oesophagus. The pressure in the oesophagus is almost the same as the pressure in the lung, and it is measured with a thin polyethylene catheter with a balloon covering the distal 10 cm. During inspiratory and expiratory manoeuvres, the changes in volume and pressure are recorded by means of a spirometer and pressure transducer, respectively. When the measurements are performed during tidal breathing, dynamic compliance can be measured. Static compliance is obtained when a slow VC manoeuvre is carried out. In the latter case, the measurements are carried out in a body plethysmograph, and the expiration is intermittently interrupted by means of a shutter. However, measurements of compliance are cumbersome to perform when examining exposure effects on lung function at the worksite, and this technique is considered to be more appropriate in the laboratory.
A decreased compliance (increased elasticity) is observed in fibrosis. To cause a change in volume, large changes in pressure are required. On the other hand, a high compliance is observed, for example, in emphysema as the result of loss of elastic tissue and therefore also elasticity in the lung.
The resistance in the airways essentially depends on the radius and length of the airways but also on air viscosity. The airway resistance (RL in (kPa/l) /s), can be determined by use of a spirometer, pressure transducer and a pneumotachograph (to measure the flow). The measurements may also be carried out using a body plethysmograph to record the changes in flow and pressure during panting manoeuvres. By administration of a drug intended to cause broncho-constriction, sensitive subjects, as a result of their hyperreactive airways, may be identified. Subjects with asthma usually have increased values for RL.
Acute and Chronic Effects of Occupational Exposure on Pulmonary Function
Lung function measurement may be used to disclose an occupational exposure effect on the lungs. Pre-employment examination of lung function should not be used to exclude job-seeking subjects. This is because the lung function of healthy subjects varies within wide limits and it is difficult to draw a borderline below which it can safely be stated that the lung is pathological. Another reason is that the work environment should be good enough to allow even subjects with slight lung function impairment to work safely.
Chronic effects on the lungs in occupationally exposed subjects may be detected in a number of ways. The techniques are designed to determine historical effects, however, and are less suitable to serve as guidelines to prevent lung function impairment. A common study design is to compare the actual values in exposed subjects with the lung function values obtained in a reference population without occupational exposure. The reference subjects may be recruited from the same (or nearby) workplaces or from the same city.
Multivariate analysis has been used in some studies to assess differences between exposed subjects and matched unexposed referents. Lung function values in exposed subjects may also be standardized by means of a reference equation based on lung function values in the unexposed subjects.
Another approach is to study the difference between the lung function values in exposed and unexposed workers after adjustment for age and height with the use of external reference values, calculated by means of a prediction equation based on healthy subjects. The reference population may also be matched to the exposed subjects according to ethnic group, sex, age, height and smoking habits in order to further control for those influencing factors.
The problem is, however, to decide if a decrease is large enough to be classified as pathological, when external reference values are being used. Although the instruments in the studies have to be portable and simple, attention must be paid both to the sensitivity of the chosen method for detecting small anomalies in airways and lungs and the possibility of combining different methods. There are indications that subjects with respiratory symptoms, such as exertion dyspnoea, are at a higher risk of having an accelerated decline in lung function. This means that the presence of respiratory symptoms is important and so should not be neglected.
The subject may also be followed-up by spirometry, for example, once a year, for a number of years, in order to give a warning against the development of illness. There are limitations, however, since this will be very time-consuming and the lung function may have deteriorated permanently when the decrease can be observed. This approach therefore must not be an excuse for delay in carrying out measures in order to decrease harmful concentrations of air pollutants.
Finally, chronic effects on lung function may also be studied by examining the individual changes in lung function in exposed and unexposed subjects over a number of years. One advantage of the longitudinal study design is that the intersubject variability is eliminated; however, the design is considered to be time-consuming and expensive.
Susceptible subjects may also be identified by comparing their lung function with and without exposure during working shifts. In order to minimize possible effects of diurnal variations, lung function is measured at the same time of day on one unexposed and one exposed occasion. The unexposed condition can be obtained, for example, by occasionally moving the worker to an uncontaminated area or by use of a suitable respirator during a whole shift, or in some cases by performing lung function measurements in the afternoon of a worker’s day off.
One special concern is that repeated, temporary effects can result in chronic effects. An acute temporary lung function decrease may not only be a biological exposure indicator but also a predictor of a chronic lung function decrement. Exposure to air pollutants may result in discernible acute effects on lung function, although the mean values of the measured air pollutants are below the hygienic limit values. The question thus arises, whether these effects really are harmful in the long run. This question is hard to answer directly, especially since the air pollution in workplaces often has a complex composition and the exposure cannot be described in terms of mean concentrations of single compounds. The effect of an occupational exposure is also partly due to the sensitivity of the individual. This means that some subjects will react sooner or to a larger extent than others. The underlying pathophysiological ground for an acute, temporary decrease in lung function is not fully understood. The adverse reaction upon exposure to an irritating air contaminant is, however, an objective measurement, in contrast to subjective experiences like symptoms of different origin.
The advantage of detecting early changes in airways and lungs caused by hazardous air pollutants is obvious—the prevailing exposure may be reduced in order to prevent more severe illnesses. Therefore, an important aim in this respect is to use the measurements of acute temporary effects on lung function as a sensitive early warning system that can be used when studying groups of healthy working people.
Monitoring of Irritants
Irritation is one of the most frequent criteria for setting exposure limit values. It is, however, not certain that compliance with an exposure limit based on irritation will protect against irritation. It should be considered that an exposure limit for an air contaminant usually contains at least two parts—a time-weighted average limit (TWAL) and a short-term exposure limit (STEL), or at least rules for exceeding the time-weighted average limit, “excursion limits”. In the case of highly irritating substances, such as sulphur dioxide, acrolein and phosgene, it is important to limit the concentration even during very short periods, and it has therefore been common practice to fix occupational exposure limit values in the form of ceiling limits, with a sampling period that is kept as short as the measuring facilities will allow.
Time-weighted average limit values for an eight-hour day combined with rules for excursion above these values are given for most of the substances in the American Conference of Governmental Industrial Hygienists (ACGIH) threshold limit value (TLV) list. The TLV list of 1993-94 contains the following statement concerning excursion limits for exceeding limit values:
“For the vast majority of substances with a TLV-TWA, there is not enough toxicological data available to warrant a STEL = short-term exposure limit). Nevertheless, excursions above the TLV-TWA should be controlled even where the eight-hour TWA is within recommended limits.”
Exposure measurements of known air contaminants and comparison with well documented exposure limit values should be carried out on a routine basis. There are, however, many situations when the determination of compliance with exposure limit values is not enough. This is the case in the following circumstances (inter alia):
As advocated above, the measurement of acute, temporary effects on lung function can be used in these cases as a warning against over-exposure to irritants.
In cases (2) and (3), acute, temporary effects on lung function may be applicable also in testing the efficiency of control measures to decrease exposure to air contamination or in scientific investigations, for example, in attributing biological effects to components of air contaminants. A number of examples follow in which acute, temporary lung function effects have been successfully employed in occupational health investigations.
Studies of Acute, Temporary Lung Function Effects
Work-related, temporary decrease of lung function over a work shift was recorded in cotton workers at the end of 1950. Later, several authors reported work-related, acute, temporary changes of lung function in hemp and textile workers, coal miners, workers exposed to toluene di-isocyanate, fire-fighters, rubber processing workers, moulders and coremakers, welders, ski waxers, workers exposed to organic dust and irritants in water-based paints.
However, there are also several examples where measurements before and after exposure, usually during a shift, have failed to demonstrate any acute effects, despite a high exposure. This is probably due to the effect of normal circadian variation, mainly in lung function variables depending on the size of airway calibre. Thus the temporary decrease in these variables must exceed the normal circadian variation to be recognized. The problem may be circumvented, however, by measuring lung function at the same time of the day at each study occasion. By using the exposed employee as his or her own control, the interindividual variation is further decreased. Welders were studied in this way, and although the mean difference between unexposed and exposed FVC values was less than 3% in 15 examined welders, this difference was significant at the 95% confidence level with a power of more than 99%.
The reversible transient effects on the lungs can be used as an exposure indicator of complicated irritating components. In the study cited above, particles in the work environment were crucial for the irritating effects on the airways and lungs. The particles were removed by a respirator consisting of a filter combined with a welding helmet. The results indicated that the effects on the lungs were caused by the particles in welding fumes, and that the use of a particulate respirator might prevent this effect.
Exposure to diesel exhaust also gives measurable irritative effects on the lungs, shown as an acute, temporary lung function decrease. Mechanical filters mounted on the exhaust pipes of trucks used in loading operations by stevedores relieved subjective disorders and reduced the acute, temporary lung function decrease observed when no filtration was done. The results thus indicate that the presence of particles in the work environment does play a role in the irritative effect on airways and lungs, and that it is possible to assess the effect by measurements of acute changes in lung function.
A multiplicity of exposures and a continually changing work environment may present difficulties in discerning the causal relationship of the different agents existing in a work environment. The exposure scenario in sawmills is an illuminating example. It is not possible (e.g., for economical reasons) to carry out exposure measurements of all possible agents (terpenes, dust, mould, bacteria, endotoxin, mycotoxins, etc.) in this work environment. A feasible method may be to follow the development of lung function longitudinally. In a study of sawmill workers in the wood-trimming department, lung function was examined before and after a working week, and no statistically significant decrease was found. However, a follow-up study carried out a few years later disclosed that those workers who actually had a numerical decrease in lung function during a working week also had an accelerated long-term decline in lung function. This may indicate that vulnerable subjects can be detected by measuring changes in lung function during a working week.
The respiratory system extends from the breathing zone just outside of the nose and mouth through the conductive airways in the head and thorax to the alveoli, where respiratory gas exchange takes place between the alveoli and the capillary blood flowing around them. Its prime function is to deliver oxygen (O2) to the gas-exchange region of the lung, where it can diffuse to and through the walls of the alveoli to oxygenate the blood passing through the alveolar capillaries as needed over a wide range of work or activity levels. In addition, the system must also: (1) remove an equal volume of carbon dioxide entering the lungs from the alveolar capillaries; (2) maintain body temperature and water vapour saturation within the lung airways (in order to maintain the viability and functional capacities of the surface fluids and cells); (3) maintain sterility (to prevent infections and their adverse consequences); and (4) eliminate excess surface fluids and debris, such as inhaled particles and senescent phagocytic and epithelial cells. It must accomplish all of these demanding tasks continuously over a lifetime, and do so with high efficiency in terms of performance and energy utilization. The system can be abused and overwhelmed by severe insults such as high concentrations of cigarette smoke and industrial dust, or by low concentrations of specific pathogens which attack or destroy its defence mechanisms, or cause them to malfunction. Its ability to overcome or compensate for such insults as competently as it usually does is a testament to its elegant combination of structure and function.
Mass Transfer
The complex structure and numerous functions of the human respiratory tract have been summarized concisely by a Task Group of the International Commission on Radiological Protection (ICRP 1994), as shown in figure 1. The conductive airways, also known as the respiratory dead space, occupy about 0.2 litres. They condition the inhaled air and distribute it, by convective (bulk) flow, to the approximately 65,000 respiratory acini leading off the terminal bronchioles. As tidal volumes increase, convective flow dominates gas exchange deeper into the respiratory bronchioles. In any case, within the respiratory acinus, the distance from the convective tidal front to alveolar surfaces is short enough so that efficient CO2-O2 exchange takes place by molecular diffusion. By contrast, airborne particles, with diffusion coefficients smaller by orders of magnitude than those for gases, tend to remain suspended in the tidal air, and can be exhaled without deposition.
Figure 1. Morphometry, cytology, histology, function and structure of the respiratory tract and regions used in the 1994 ICRP dosimetry model.
A significant fraction of the inhaled particles do deposit within the respiratory tract. The mechanisms accounting for particle deposition in the lung airways during the inspiratory phase of a tidal breath are summarized in figure 2. Particles larger than about 2 mm in aerodynamic diameter (diameter of a unit density sphere having the same terminal settling (Stokes) velocity) can have significant momentum and deposit by impaction at the relatively high velocities present in the larger airways. Particles larger than about 1 mm can deposit by sedimentation in the smaller conductive airways, where flow velocities are very low. Finally, particles with diameters between 0.1 and 1 mm, which have a very low probability of depositing during a single tidal breath, can be retained within the approximately 15% of the inspired tidal air that is exchanged with residual lung air during each tidal cycle. This volumetric exchange occurs because of the variable time-constants for airflow in the different segments of the lungs. Due to the much longer residence times of the residual air in the lungs, the low intrinsic particle displacements of 0.1 to 1 mm particles within such trapped volumes of inhaled tidal air become sufficient to cause their deposition by sedimentation and/or diffusion over the course of successive breaths.
Figure 2. Mechanisms for particle deposition in lung airways
The essentially particle-free residual lung air that accounts for about 15% of the expiratory tidal flow tends to act like a clean-air sheath around the axial core of distally moving tidal air, such that particle deposition in the respiratory acinus is concentrated on interior surfaces such as airway bifurcations, while interbranch airway walls have little deposition.
The number of particles deposited and their distribution along the respiratory tract surfaces are, along with the toxic properties of the material deposited, the critical determinants of pathogenic potential. The deposited particles can damage the epithelial and/or the mobile phagocytic cells at or near the deposition site, or can stimulate the secretion of fluids and cell-derived mediators that have secondary effects on the system. Soluble materials deposited as, on, or within particles can diffuse into and through surface fluids and cells and be rapidly transported by the bloodstream throughout the body.
Aqueous solubility of bulk materials is a poor guide to particle solubility in the respiratory tract. Solubility is generally greatly enhanced by the very large surface-to-volume ratio of particles small enough to enter the lungs. Furthermore, the ionic and lipid contents of surface fluids within the airways are complex and highly variable, and can lead to either enhanced solubility or to rapid precipitation of aqueous solutes. Furthermore, the clearance pathways and residence times for particles on airway surfaces are very different in the different functional parts of the respiratory tract.
The revised ICRP Task Group’s clearance model identifies the principal clearance pathways within the respiratory tract that are important in determining the retention of various radioactive materials, and thus the radiation doses received by respiratory tissues and other organs after translocation. The ICRP deposition model is used to estimate the amount of inhaled material that enters each clearance pathway. These discrete pathways are represented by the compartment model shown in figure 3. They correspond to the anatomic compartments illustrated in Figure 1, and are summarized in table 1, along with those of other groups providing guidance on the dosimetry of inhaled particles.
Figure 3. Compartment model to represent time-dependent particle transport from each region in 1994 ICRP model
Table 1. Respiratory tract regions as defined in particle deposition models
Anatomic structures included | ACGIH Region | ISO and CEN Regions | 1966 ICRP Task Group Region | 1994 ICRP Task Group Region |
Nose, nasopharynx Mouth, oropharynx, laryngopharynx |
Head airways (HAR) | Extrathoracic (E) | Nasopharynx (NP) | Anterior nasal passages (ET1 ) All other extrathoracic (ET2 ) |
Trachea, bronchi | Tracheobronchial (TBR) | Tracheobronchial (B) | Tracheobronchial (TB) | Trachea and large bronchi (BB) |
Bronchioles (to terminal bronchioles) | Bronchioles (bb) | |||
Respiratory bronchioles, alveolar ducts, alveolar sacs, alveoli |
Gas exchange (GER) | Alveolar (A) | Pulmonary (P) | Alveolar-interstitial (AI) |
Extrathoracic airways
As shown in figure 1, the extrathoracic airways were partitioned by ICRP (1994) into two distinct clearance and dosimetric regions: the anterior nasal passages (ET1) and all other extrathoracic airways (ET2)—that is, the posterior nasal passages, the naso- and oropharynx, and the larynx. Particles deposited on the surface of the skin lining the anterior nasal passages (ET1) are assumed to be subject only to removal by extrinsic means (nose blowing, wiping and so on). The bulk of material deposited in the naso-oropharynx or larynx (ET2) is subject to fast clearance in the layer of fluid that covers these airways. The new model recognizes that diffusional deposition of ultrafine particles in the extrathoracic airways can be substantial, while the earlier models did not.
Thoracic airways
Radioactive material deposited in the thorax is generally divided between the tracheobronchial (TB) region, where deposited particles are subject to relatively fast mucociliary clearance, and the alveolar-interstitial (AI) region, where the particle clearance is much slower.
For dosimetry purposes, the ICRP (1994) divided deposition of inhaled material in the TB region between the trachea and bronchi (BB), and the more distal, small airways, the bronchioles (bb). However, the subsequent efficiency with which cilia in either type of airways are able to clear deposited particles is controversial. In order to be certain that doses to bronchial and bronchiolar epithelia would not be underestimated, the Task Group assumed that as much as half the number of particles deposited in these airways is subject to relatively “slow” mucociliary clearance. The likelihood that a particle is cleared relatively slowly by the mucociliary system appears to depend on its physical size.
Material deposited in the AI region is subdivided among three compartments (AI1, AI2 and AI3) that are each cleared more slowly than TB deposition, with the subregions cleared at different characteristic rates.
Figure 4. Fractional deposition in each region of respiratory tract for reference light worker (normal nose breather) in 1994 ICRP model.
Figure 4 depicts the predictions of the ICRP (1994) model in terms of the fractional deposition in each region as a function of the size of the inhaled particles. It reflects the minimal lung deposition between 0.1 and 1 mm, where deposition is determined largely by the exchange, in the deep lung, between tidal and residual lung air. Deposition increases below 0.1 mm as diffusion becomes more efficient with decreasing particle size. Deposition increases with increasing particle size above 1 mm as sedimentation and impaction become increasingly effective.
Less complex models for size-selective deposition have been adopted by occupational health and community air pollution professionals and agencies, and these have been used to develop inhalation exposure limits within specific particle size ranges. Distinctions are made between:
In the early 1990s there has been an international harmonization of the quantitative definitions of IPM, TPM and RPM. The size-selective inlet specifications for air samplers meeting the criteria of the American Conference of Governmental Industrial Hygienists (ACGIH 1993), the International Organization for Standardization (ISO 1991) and the European Standardization Committee (CEN 1991) are enumerated in table 2. They differ from the deposition fractions of ICRP (1994), especially for larger particles, because they take the conservative position that protection should be provided for those engaged in oral inhalation, and thereby bypass the more efficient filtration efficiency of the nasal passages.
Table 2. Inhalable, thoracic and respirable dust criteria of ACGIH, ISO and CEN, and PM10 criteria of US EPA
Inhalable | Thoracic | Respirable | PM10 | ||||
Particle aero- dynamic diameter (mm) |
Inhalable Particulate Mass (IPM) (%) |
Particle aero- dynamic diameter (mm) |
Thoracic Particulate Mass (TPM) (%) |
Particle aero- dynamic diameter (mm) |
Respirable Particulate Mass (RPM) (%) |
Particle aero- dynamic diameter (mm) |
Thoracic Particulate Mass (TPM) (%) |
0 | 100 | 0 | 100 | 0 | 100 | 0 | 100 |
1 | 97 | 2 | 94 | 1 | 97 | 2 | 94 |
2 | 94 | 4 | 89 | 2 | 91 | 4 | 89 |
5 | 87 | 6 | 80.5 | 3 | 74 | 6 | 81.2 |
10 | 77 | 8 | 67 | 4 | 50 | 8 | 69.7 |
20 | 65 | 10 | 50 | 5 | 30 | 10 | 55.1 |
30 | 58 | 12 | 35 | 6 | 17 | 12 | 37.1 |
40 | 54.5 | 14 | 23 | 7 | 9 | 14 | 15.9 |
50 | 52.5 | 16 | 15 | 8 | 5 | 16 | 0 |
100 | 50 | 18 | 9.5 | 10 | 1 | ||
20 | 6 | ||||||
25 | 2 |
The US Environmental Protection Agency (EPA 1987) standard for ambient air particle concentration is known as PM10, that is, particulate matter less than 10 mm in aerodynamic diameter. It has a sampler inlet criterion that is similar (functionally equivalent) to TPM but, as shown in Table 2, somewhat different numerical specifications.
Air Pollutants
Pollutants can be dispersed in air at normal ambient temperatures and pressures in gaseous, liquid and solid forms. The latter two represent suspensions of particles in air and were given the generic term aerosols by Gibbs (1924) on the basis of analogy to the term hydrosol, used to describe dispersed systems in water. Gases and vapours, which are present as discrete molecules, form true solutions in air. Particles consisting of moderate to high vapour pressure materials tend to evaporate rapidly, because those small enough to remain suspended in air for more than a few minutes (i.e., those smaller than about 10 mm) have large surface-to-volume ratios. Some materials with relatively low vapour pressures can have appreciable fractions in both vapour and aerosol forms simultaneously.
Gases and vapours
Once dispersed in air, contaminant gases and vapours generally form mixtures so dilute that their physical properties (such as density, viscosity, enthalpy and so on) are indistinguishable from those of clean air. Such mixtures may be considered to follow ideal gas law relationships. There is no practical difference between a gas and a vapour except that the latter is generally considered to be the gaseous phase of a substance that can exist as a solid or liquid at room temperature. While dispersed in air, all molecules of a given compound are essentially equivalent in their size and probabilities of capture by ambient surfaces, respiratory tract surfaces and contaminant collectors or samplers.
Aerosols
Aerosols, being dispersions of solid or liquid particles in air, have the very significant additional variable of particle size. Size affects particle motion and, hence, the probabilities of physical phenomena such as coagulation, dispersion, sedimentation, impaction onto surfaces, interfacial phenomena and light-scattering properties. It is not possible to characterize a given particle by a single size parameter. For example, a particle’s aerodynamic properties depend on density and shape as well as linear dimensions, and the effective size for light scattering is dependent on refractive index and shape.
In some special cases, all of the particles are essentially the same in size. Such aerosols are considered to be monodisperse. Examples are natural pollens and some laboratory-generated aerosols. More typically, aerosols are composed of particles of many different sizes and hence are called heterodisperse or polydisperse. Different aerosols have different degrees of size dispersion. It is, therefore, necessary to specify at least two parameters in characterizing aerosol size: a measure of central tendency, such as a mean or median, and a measure of dispersion, such as an arithmetic or geometric standard deviation.
Particles generated by a single source or process generally have diameters following a log-normal distribution; that is, the logarithms of their individual diameters have a Gaussian distribution. In this case, the measure of dispersion is the geometric standard deviation, which is the ratio of the 84.1 percentile size to the 50 percentile size. When more than one source of particles is significant, the resulting mixed aerosol will usually not follow a single log-normal distribution, and it may be necessary to describe it by the sum of several distributions.
Particle characteristics
There are many properties of particles other than their linear size that can greatly influence their airborne behaviour and their effects on the environment and health. These include:
Surface. For spherical particles, the surface varies as the square of the diameter. However, for an aerosol of given mass concentration, the total aerosol surface increases with decreasing particle size. For non-spherical or aggregate particles, and for particles with internal cracks or pores, the ratio of surface to volume can be much greater than for spheres.
Volume. Particle volume varies as the cube of the diameter; therefore, the few largest particles in an aerosol tend to dominate its volume (or mass) concentration.
Shape. A particle’s shape affects its aerodynamic drag as well as its surface area and therefore its motion and deposition probabilities.
Density. A particle’s velocity in response to gravitational or inertial forces increases as the square root of its density.
Aerodynamic diameter. The diameter of a unit-density sphere having the same terminal settling velocity as the particle under consideration is equal to its aerodynamic diameter. Terminal settling velocity is the equilibrium velocity of a particle that is falling under the influence of gravity and fluid resistance. Aerodynamic diameter is determined by the actual particle size, the particle density and an aerodynamic shape factor.
Types of aerosols
Aerosols are generally classified in terms of their processes of formation. Although the following classification is neither precise nor comprehensive, it is commonly used and accepted in the industrial hygiene and air pollution fields.
Dust. An aerosol formed by mechanical subdivision of bulk material into airborne fines having the same chemical composition. Dust particles are generally solid and irregular in shape and have diameters greater than 1 mm.
Fume. An aerosol of solid particles formed by condensation of vapours formed by combustion or sublimation at elevated temperatures. The primary particles are generally very small (less than 0.1 mm) and have spherical or characteristic crystalline shapes. They may be chemically identical to the parent material, or may be composed of an oxidation product such as metal oxide. Since they may be formed in high number concentrations, they often rapidly coagulate, forming aggregate clusters of low overall density.
Smoke. An aerosol formed by condensation of combustion products, generally of organic materials. The particles are generally liquid droplets with diameters less than 0.5 mm.
Mist. A droplet aerosol formed by mechanical shearing of a bulk liquid, for example, by atomization, nebulization, bubbling or spraying. The droplet size can cover a very large range, usually from about 2 mm to greater than 50 mm.
Fog. An aqueous aerosol formed by condensation of water vapour on atmospheric nuclei at high relative humidities. The droplet sizes are generally greater than 1 mm.
Smog. A popular term for a pollution aerosol derived from a combination of smoke and fog. It is now commonly used for any atmospheric pollution mixture.
Haze. A submicrometer-sized aerosol of hygroscopic particles that take up water vapour at relatively low relative humidities.
Aitken or condensation nuclei (CN). Very small atmospheric particles (mostly smaller than 0.1 mm) formed by combustion processes and by chemical conversion from gaseous precursors.
Accumulation mode. A term given to the particles in the ambient atmosphere ranging from 0.1 to about 1.0 mm in diameter. These particles generally are spherical (having liquid surfaces), and form by coagulation and condensation of smaller particles that derive from gaseous precursors. Being too large for rapid coagulation and too small for effective sedimentation, they tend to accumulate in the ambient air.
Coarse particle mode. Ambient air particles larger than about 2.5 mm in aerodynamic diameter and generally formed by mechanical processes and surface dust resuspension.
Biological Responses of the Respiratory System to Air Pollutants
Responses to air pollutants range from nuisance to tissue necrosis and death, from generalized systemic effects to highly specific attacks on single tissues. Host and environmental factors serve to modify the effects of inhaled chemicals, and the ultimate response is the result of their interaction. The main host factors are:
The environmental factors include the concentration, stability and physicochemical properties of the agent in the exposure environment and the duration, frequency and route of exposure. Acute and chronic exposures to a chemical may result in different pathological manifestations.
Any organ can respond in only a limited number of ways, and there are numerous diagnostic labels for the resultant diseases. The following sections discuss the broad types of responses of the respiratory system which may occur following exposure to environmental pollutants.
Irritant response
Irritants produce a pattern of generalized, non-specific tissue inflammation, and destruction may result at the area of contaminant contact. Some irritants produce no systemic effect because the irritant response is much greater than any systemic effect, while some also have significant systemic effects following absorption—for example, hydrogen sulphide absorbed via the lungs.
At high concentrations, irritants may cause a burning sensation in the nose and throat (and usually also in the eyes), pain in the chest and coughing producing inflammation of the mucosa (tracheitis, bronchitis). Examples of irritants are gases such as chlorine, fluorine, sulphur dioxide, phosgene and oxides of nitrogen; mists of acids or alkali; fumes of cadmium; dusts of zinc chloride and vanadium pentoxide. High concentrations of chemical irritants may also penetrate deep into the lungs and cause lung oedema (the alveoli are filled with liquid) or inflammation (chemical pneumonitis).
Highly elevated concentrations of dusts which have no chemical irritative properties can also mechanically irritate bronchi and, after entering the gastrointestinal tract, may also contribute to stomach and colon cancer.
Exposure to irritants may result in death if critical organs are severely damaged. On the other hand, the damage may be reversible, or it may result in permanent loss of some degree of function, such as impaired gas-exchange capacity.
Fibrotic response
A number of dusts lead to the development of a group of chronic lung disorders termed pneumoconioses. This general term encompasses many fibrotic conditions of the lung, that is, diseases characterized by scar formation in the interstitial connective tissue. Pneumoconioses are due to the inhalation and subsequent selective retention of certain dusts in the alveoli, from which they are subject to interstitial sequestration.
Pneumoconioses are characterized by specific fibrotic lesions, which differ in type and pattern according to the dust involved. For example, silicosis, due to the deposition of crystalline-free silica, is characterized by a nodular type of fibrosis, while a diffuse fibrosis is found in asbestosis, due to asbestos-fibre exposure. Certain dusts, such as iron oxide, produce only altered radiology (siderosis) with no functional impairment, while the effects of others range from a minimal disability to death.
Allergic response
Allergic responses involve the phenomenon known as sensitization. Initial exposure to an allergen results in the induction of antibody formation; subsequent exposure of the now “sensitized” individual results in an immune response—that is, an antibody-antigen reaction (the antigen is the allergen in combination with an endogenous protein). This immune reaction may occur immediately following exposure to the allergen, or it may be a delayed response.
The primary respiratory allergic reactions are bronchial asthma, reactions in the upper respiratory tract which involve the release of histamine or histamine-like mediators following immune reactions in the mucosa, and a type of pneumonitis (lung inflammation) known as extrinsic allergic alveolitis. In addition to these local reactions, a systemic allergic reaction (anaphylactic shock) may follow exposure to some chemical allergens.
Infectious response
Infectious agents can cause tuberculosis, anthrax, ornithosis, brucellosis, histoplasmosis, Legionnaires’ disease and so on.
Carcinogenic response
Cancer is a general term for a group of related diseases characterized by the uncontrolled growth of tissues. Its development is due to a complex process of interacting multiple factors in the host and the environment.
One of the great difficulties in attempting to relate exposure to a specific agent to cancer development in humans is the long latent period, typically from 15 to 40 years, between onset of exposure and disease manifestation.
Examples of air pollutants that can produce cancer of the lungs are arsenic and its compounds, chromates, silica, particles containing polycyclic aromatic hydrocarbons and certain nickel-bearing dusts. Asbestos fibres can cause bronchial cancer and mesothelioma of the pleura and peritoneum. Deposited radioactive particles may expose lung tissue to high local doses of ionizing radiation and be the cause of cancer.
Systemic response
Many environmental chemicals produce a generalized systemic disease due to their effects upon a number of target sites. Lungs are not only the target for many harmful agents but the site of entry of toxic substances which pass through the lungs into the bloodstream without any damage to the lungs. However, when distributed by the blood circulation to various organs, they can damage them or cause general poisoning and have systemic effects. This role of the lungs in occupational pathology is not the subject of this article. However, the effect of finely dispersed particulates (fumes) of several metal oxides which are often associated with an acute systemic syndrome known as metal fume fever should be mentioned.
Table 5. List of of technical products unlikely to present acute hazard in normal use (continued)
Name | Status | Main use | Chemical type | Physical state | Route | LD50 (mg/kg) | Remarks |
Hexaconazole |
N(B) |
F |
S |
O |
2,180 |
||
Hexaflumuron |
ISO |
I |
S |
O |
+5,000 |
||
Hexythiazox |
N(B) |
AC |
S |
O |
+5,000 |
||
Hydroprene |
N(A) |
IGR |
L |
O |
+10,000 |
||
2-Hydroxyethyl octyl sulphide |
C |
RP (insect) |
L |
O |
8,530 |
||
Hydroxyisoxazole |
N(J) |
See hymexazol |
|||||
Hymexazol |
N(B) |
FST |
S |
O |
3,900 |
||
Imazamethabenz-methyl |
(ISO) |
H |
S |
O |
+5,000 |
||
Imazapyr |
ISO |
H |
S |
O |
+5,000 |
Irritant to eyes |
|
Imazaquin |
ISO |
H |
S |
O |
+5,000 |
||
Imazethapyr |
N(B) |
H |
S |
O |
+5,000 |
||
Imibenconazole |
ISO |
F |
S |
O |
+5,000 |
||
Inabenfide |
ISO |
PGR |
S |
O |
+10,000 |
||
Iodofenphos |
N(A,B) |
See jodfenphos |
|||||
Iprodione |
ISO |
F |
S |
O |
3,500 |
||
Isopropalin |
ISO |
H |
L |
O |
+5,000 |
||
Isoxaben |
N(B) |
H |
S |
O |
+10,000 |
||
Jodfenphos |
ISO |
I |
OP |
S |
O |
2,100 |
DS 43 |
Karbutilate |
ISO |
H |
S |
O |
3,000 |
||
Kasugamycin |
N(J) |
F |
S |
O |
+10,000 |
||
Kinoprene |
ISO |
IGR |
S |
O |
4,900 |
||
Lenacil |
ISO |
H |
S |
O |
+10,000 |
||
Linuron |
ISO |
H |
S |
O |
4,000 |
||
Maleic hydrazide |
ISO |
PGR |
S |
O |
6,950 |
||
Mancozeb |
ISO |
F |
TC |
S |
O |
+8,000 |
Irritant to skin on multiple exposure; DS 94 |
Maneb |
ISO |
F |
TC |
S |
O |
6,750 |
Irritant to skin on multiple exposure; DS 94 |
Mefenacet |
ISO |
H |
S |
O |
+5,000 |
||
Mepanipyrim |
ISO |
F |
S |
O |
+5,000 |
||
Mepronil |
N(J) |
F |
S |
O |
+10,000 |
||
Metamitron |
ISO |
H |
S |
O |
3,343 |
||
Metazachlor |
ISO |
H |
S |
O |
2,150 |
||
Methabenzthiazuron |
ISO |
H |
S |
O |
+2,500 |
||
Methoprene |
ISO |
IGR |
L |
O |
+10,000 |
DS 47 |
|
Methoprotryne |
ISO |
H |
S |
O |
+5,000 |
||
Methoxychlor |
ISO |
I |
OC |
S |
O |
6,000 |
DS 28 |
Methoxyphenone |
N(J) |
H |
S |
O |
+4,000 |
||
Methyldymron |
N(J) |
H |
S |
O |
3,948 |
||
Metiram |
N(J) |
F |
S |
O |
+10,000 |
||
Metobromuron |
ISO |
H |
S |
O |
2,500 |
||
Metosulam |
ISO |
H |
S |
O |
+5,000 |
||
Metoxuron |
ISO |
H |
S |
O |
+3,200 |
||
Metribuzin |
ISO |
H |
T |
S |
O |
2,200 |
|
Metsulfovax |
ISO |
F |
S |
O |
3,929 |
||
Metsulfuron |
N(A,B) |
H |
S |
O |
+5,000 |
||
Monalide |
ISO |
H |
S |
O |
+4,000 |
||
Monolinuron |
ISO |
H |
S |
O |
2,250 |
||
Monuron |
ISO |
H |
S |
O |
3,600 |
||
Monuron-TCA |
N(A) |
H |
S |
O |
3,700 |
||
Naphthalene |
C |
F |
S |
O |
2,200 |
||
Naphthalic anhydride |
C |
PGR |
S |
O |
+10,000 |
||
2-(1-naphthyl) acetamide |
ISO |
PGR |
S |
O |
6,400 |
||
1-naphthylacetic acid |
ISO |
PGR |
S |
O |
c3,000 |
||
Napropamide |
ISO |
H |
S |
O |
5,000 |
||
Naptalam |
ISO |
PGR |
S |
O |
8,200 |
||
Neburon |
ISO |
H |
S |
O |
+10,000 |
||
Niclosamide |
ISO |
M |
S |
O |
5,000 |
DS 63 |
|
Nicosulfuron |
ISO |
H |
S |
O |
+5,000 |
Irritant to eyes |
|
Nitralin |
ISO |
H |
S |
O |
+2,000 |
||
Nitrothal-isopropyl |
ISO |
F |
S |
O |
6,400 |
||
Norflurazon |
ISO |
H |
S |
O |
+8,000 |
||
(octylthio)ethanol |
C |
See 2-hydroxyethyl octyl sulphide |
|||||
Ofurace |
ISO |
F |
S |
O |
2,600 |
||
Oryzalin |
ISO |
H |
S |
O |
+10,000 |
||
Oxabetrinil |
ISO |
H |
S |
O |
+5,000 |
||
Oxadiazon |
ISO |
H |
S |
O |
+8,000 |
||
Oxine copper |
ISO |
F |
S |
O |
10,000 |
||
Oxycarboxin |
ISO |
F |
S |
O |
2,000 |
||
Oxyfluorfen |
ISO |
H |
S |
O |
+5,000 |
||
Penconazole |
N(B) |
F |
S |
O |
2,120 |
||
Pencycuron |
ISO |
F |
S |
O |
+5,000 |
||
Pentanochlor |
ISO |
H |
S |
O |
+10,000 |
||
Phenisobromolate |
N(J) |
See bromopropylate |
|||||
Phenisopham |
ISO |
H |
S |
O |
+4,000 |
||
Phenmedipham |
ISO |
H |
S |
O |
+8,000 |
||
Phenothrin |
ISO |
I |
PY |
L |
O |
+5,000 |
DS 85; EHC 96; HSG 32 |
2-Phenylphenol |
ISO |
F |
S |
O |
2,480 |
||
Phosdiphen |
N(J) |
F |
L |
O |
6,200 |
||
Phthalide |
N(J) |
F |
S |
O |
+10,000 |
||
Picloram |
ISO |
H |
S |
O |
8,200 |
||
Piperonyl butoxide |
N(A) |
SY |
oil |
O |
+7,500 |
||
Pretilachlor |
ISO |
H |
L |
O |
6,100 |
||
Primisulfuron |
ISO |
H |
S |
O |
+5,050 |
||
Probenazole |
N(J) |
F |
S |
O |
2,030 |
||
Procymidone |
ISO |
F |
S |
O |
6,800 |
||
Prodiamine |
ISO |
H |
S |
O |
+5,000 |
||
Profluralin |
ISO |
H |
S |
O |
c10,000 |
||
Proglinazine |
ISO |
H |
S |
O |
+8,000 |
||
Prometon |
ISO |
H |
T |
S |
O |
2,980 |
|
Prometryn |
ISO |
H |
T |
S |
O |
3,150 |
|
Pronamide |
N(A) |
See propyzamide |
|||||
Propamocarb |
ISO |
F |
S |
O |
8,600 |
||
Propaquizafop |
ISO |
H |
S |
O |
+5,000 |
||
Propazine |
ISO |
H |
T |
S |
O |
+5,000 |
|
Propham |
ISO |
H |
S |
O |
5,000 |
||
Propineb |
ISO |
H |
TC |
S |
O |
8,500 |
|
Propyzamide |
ISO |
H |
S |
O |
5,620 |
||
Pyracarbolid |
ISO |
F |
S |
O |
+10,000 |
||
Pyrazolynate |
ISO |
H |
S |
O |
9,550 |
||
Pyrazon |
N(A) |
See chloridazon |
|||||
Pyrazosulfuron |
ISO |
H |
S |
O |
+5,000 |
||
Pyrimethanil |
ISO |
F |
S |
O |
4,150 |
||
Pyriminobac |
ISO |
H |
S |
O |
+5,000 |
||
Pyriproxyfen |
N(B) |
I |
S |
O |
+5,000 |
||
Quinclorac |
ISO |
H |
S |
O |
2,680 |
||
Quinmerac |
ISO |
H |
S |
O |
+5,000 |
||
Quinomethinoate |
N(B) |
See chinomethionat |
|||||
Quinonamid |
ISO |
F |
S |
O |
+10,000 |
||
Quintozene |
ISO |
F |
S |
O |
+10,000 |
EHC 41 |
|
Rimsulfuron |
C |
H |
S |
O |
+5,000 |
||
Secbumeton |
ISO |
H |
T |
S |
O |
2,680 |
|
Siduron |
ISO |
H |
S |
O |
+7,500 |
||
Simazine |
ISO |
H |
T |
S |
O |
+5,000 |
|
Sodium metaborate |
C |
See borax |
|||||
Sodium trichloracetate |
The data shown refer to sodium trichloroacetic acid. In many countries, the term TCA refers to the free acid (now accepted by ISO): this is a solid with an oral LD50 of 400 mg/kg and if used as a pesticide is placed in Class II. It is highly corrosive to skin |
||||||
Solan |
N(A) |
See pentanochlor |
|||||
Stirofos |
N(A) |
See tetrachlorvinphos |
|||||
Sulfometuron |
N(B) |
H |
S |
O |
+5,000 |
||
Sulfur |
N(A,J) |
See sulphur |
|||||
Sulphur |
ISO |
F,I |
S |
O |
+3,000 |
Irritant to skin and mucous membranes. Sulphur dust can spontaneously ignite unless diluted about 50% with inert material |
|
TCA |
ISO |
H |
S |
O |
3,200 |
Irritant to skin and eyes; see sodium trichloracetate |
|
Tebuconazole |
ISO |
F |
S |
O |
4,000 |
||
Tebutam |
ISO |
H |
oil |
O |
6,210 |
||
Tecnazene |
ISO |
F |
S |
O |
+10,000 |
EHC 42; HSG 12 |
|
Tedion |
N(U) |
See tetradifon |
|||||
Teflubenzuron |
N(B) |
I |
S |
O |
+5,000 |
||
Temephos |
ISO |
I |
OP |
L |
O |
8,600 |
DS 8 |
Terbacil |
ISO |
H |
S |
O |
+5,000 |
||
Terbuthylazine |
ISO |
H |
T |
S |
O |
2,160 |
|
Terbutryn |
ISO |
H |
T |
S |
O |
2,400 |
|
Tetrachlorvinphos |
ISO |
I |
OP |
S |
O |
4,000 |
|
Tetradifon |
ISO |
AC |
S |
O |
+10,000 |
EHC 67; HSG 11 |
|
Tetramethrin |
ISO |
O |
PY |
S |
O |
+5,000 |
EHC 98; HSG 31 |
Tetrasul |
ISO |
AC |
S |
O |
6,810 |
||
Thiabendazole |
ISO |
F |
S |
O |
3,330 |
||
Thidiazuron |
ISO |
PGR |
S |
O |
+4,000 |
||
Thifensulfuron |
N(B) |
H |
S |
O |
+5,000 |
||
Thiophanate |
ISO |
F |
S |
O |
+10,000 |
||
Thiophanate-methyl |
ISO |
F |
S |
O |
+6,000 |
||
Tiocarbazil |
ISO |
H |
TC |
L |
O |
10,000 |
|
Tolclofos-methyl |
ISO |
F-S |
S |
O |
c5,000 |
||
Tolyfluanid |
ISO |
F |
S |
O |
+5,000 |
||
Transfluthrin |
ISO |
I |
PY |
S |
O |
+5,000 |
|
Triasulfuron |
ISO |
H |
S |
O |
+5,000 |
||
Tribenuron |
N(B) |
H |
S |
O |
+5,000 |
||
Trichlamide |
ISO |
F |
S |
O |
+5,000 |
||
Trietazine |
ISO |
H |
T |
S |
O |
2,830 |
|
Trifluralin |
ISO |
H |
S |
O |
+10,000 |
||
Triflumuron |
ISO |
PGR |
S |
O |
+5,000 |
||
Triforine |
ISO |
F |
S |
O |
+6,000 |
||
Triticonazole |
N(B) |
F |
triazole |
S |
O |
+2,000 |
|
Validamycin |
N(J) |
F |
S |
O |
+10,000 |
||
Vinclozolin |
ISO |
F |
S |
O |
10,000 |
||
Zineb |
ISO |
F |
S |
O |
+5,000 |
DS 94 |
Source: WHO 1996.
Table 5. List of technical products unlikely to present acute hazard in normal use
Name |
Status |
Main use |
Chemical type |
Physical state |
Route |
LD50 (mg/kg) |
Remarks |
Aclonifen |
N(B) |
H |
S |
O |
+5,000 |
||
Acrinathrin |
ISO |
MT |
S |
O |
+5,000 |
||
Alloxydim |
ISO |
H |
S |
O |
2,260 |
||
Aminotriazole |
N(F) |
See amitrole |
|||||
Amitrole |
ISO |
H |
T |
S |
O |
5,000 |
EHC 158, DS 79; HSG 85 |
Ammonium sulfamate |
ISO |
H |
S |
O |
3,900 |
||
Ancymidol |
ISO |
PGR |
S |
O |
4,500 |
||
Anilazine |
ISO |
F |
T |
S |
O |
2,710 |
Irritant to eyes and skin |
Anthraquinone |
ISO |
RP (birds) |
S |
O |
+5,000 |
||
Asulam |
ISO |
H |
TC |
S |
O |
+4,000 |
|
Atrazine |
ISO |
H |
T |
S |
O |
c2,000 |
DS 82; HSG 47 |
Aziprotryne |
ISO |
H |
T |
S |
O |
3,600 |
|
Benalaxyl |
ISO |
F |
S |
O |
c4,200 |
||
Benazolin |
ISO |
H |
S |
O |
3,200 |
Irritant to skin and eyes |
|
Benefin |
N(A) |
See benfluralin |
|||||
Benfluralin |
ISO |
H |
S |
O |
+10,000 |
||
Benfuresate |
ISO |
H |
S |
O |
2,031 |
||
Benomyl |
ISO |
F |
TC |
S |
O |
+10,000 |
EHC 148, DS 87; HSG 81 |
Benoxacor |
ISO |
H |
S |
O |
+5,000 |
||
Bensulfuron |
N(B) |
H |
S |
O |
+5,000 |
||
Benthrodine |
N(J) |
See benfluralin |
|||||
Benzamizole |
See isoxaben |
||||||
Benzoximate |
ISO |
AC |
S |
O |
+10,000 |
||
Bifenox |
ISO |
H |
S |
O |
+6,400 |
||
Bioresmethrin |
ISO |
I |
PY |
L |
O |
+7,000 |
DS 34 |
Biphenyl |
ISO |
F |
S |
O |
3,280 |
||
Bispyribac |
ISO |
H |
S |
O |
2,635 |
||
Bitertanol |
ISO |
F |
S |
O |
+5,000 |
||
Borax |
ISO |
F |
S |
O |
4,500 |
||
Bromacil |
ISO |
H |
S |
O |
5,200 |
||
Bromobutide |
ISO |
H |
S |
O |
+5,000 |
||
Bromocyclen |
ISO |
I,AC |
S |
O |
+10,000 |
||
Bromopropylate |
ISO |
AC |
S |
O |
+5,000 |
||
Bupirimate |
ISO |
F |
S |
O |
c4,000 |
||
Buprofezin |
ISO |
I |
S |
O |
2,200 |
||
Butachlor |
ISO |
H |
L |
O |
3,300 |
||
Buthiobate |
ISO |
F |
L |
O |
3,200 |
||
Butopyronoxyl |
N(A) |
RP (insects) |
L |
O |
7,840 |
||
Butralin |
ISO |
H |
S |
O |
+10,000 |
||
Buturon |
ISO |
H |
S |
O |
3,000 |
||
Butylate |
ISO |
F |
TC |
L |
O |
+4,000 |
|
Captan |
ISO |
F |
S |
O |
9,000 |
Irritant to skin; DS 9; HSG 50 |
|
Carbendazim |
ISO |
F |
S |
O |
+10,000 |
DS 89; EHC 149; HSG 82 |
|
Carbetamide |
ISO |
H |
S |
O |
+10,000 |
||
Carboxin |
ISO |
FST |
S |
O |
3,820 |
||
Chinomethionat |
ISO |
AC,F |
S |
O |
2,500 |
||
Chlomethoxyfen |
N(B) |
H |
S |
O |
+10,000 |
||
Chloramben |
ISO |
H |
S |
O |
5,620 |
||
Chlorbromuron |
ISO |
H |
S |
O |
+5,000 |
||
Chlorbufam |
ISO |
H |
S |
O |
2,500 |
||
Chlorfenidim |
N(U) |
See monuron |
|||||
Chlorfluazuron |
ISO |
IGR |
S |
O |
8,500 |
||
Chlorflurecol |
N(B) |
See chlorflurenol |
|||||
Chlorflurenol |
ISO |
PGR |
OC |
S |
O |
+10,000 |
|
Chloridazon |
ISO |
H |
S |
O |
2,420 |
||
Chlorimuron |
N(B) |
H |
S |
O |
4,102 |
||
Chlornitrofen |
ISO |
H |
S |
O |
+10,000 |
||
Chloromethiuron |
ISO |
Ix |
S |
O |
2,500 |
||
Chloroneb |
ISO |
H |
OC |
S |
O |
+10,000 |
|
Chloropropylate |
ISO |
AC |
OC |
S |
O |
+5,000 |
|
Chlorothalonil |
ISO |
F |
S |
O |
+10,000 |
||
Chlorotoluron |
ISO |
H |
S |
O |
+10,000 |
||
Chloroxifenidim |
N(U) |
See chloroxuron |
|||||
Chloroxuron |
ISO |
H |
S |
O |
+3,000 |
||
Chlorphoxim |
ISO |
I |
OP |
S |
O |
+2,500 |
DS 32 |
Chlorpropham |
ISO |
H |
S |
O |
+5,000 |
||
Chlorpyrifos methyl |
ISO |
I |
OP |
L |
O |
+3,000 |
DS 33 |
Chlorsulfuron |
ISO |
H |
S |
O |
5,545 |
||
Chlorthal-dimethyl |
ISO |
H |
S |
O |
+3,000 |
||
Chlozolinate |
N(B) |
F |
S |
O |
+4,000 |
||
Cinmethylin |
ISO |
H |
L |
O |
3,960 |
||
Cinosulfuron |
ISO |
H |
S |
O |
+5,000 |
||
Clofentezine |
N(B) |
AC |
S |
O |
+5,200 |
||
Clomeprop |
ISO |
H |
S |
O |
+5,000 |
||
Clonitralide |
N(A) |
See niclosamide |
|||||
Clopyralid |
N(B) |
H |
S |
O |
4,300 |
Severe irritant to eyes |
|
Cloxyfonac |
ISO |
PGR |
S |
O |
+5,000 |
||
CNA |
N(J) |
See dicloran |
|||||
COMU |
N(J) |
See cycluron |
|||||
Credazine |
N(J) |
H |
S |
O |
3,090 |
||
Cryolite |
C |
I |
S |
O |
+10,000 |
||
Cycloprothrin |
ISO |
I |
PY |
L |
O |
+5,000 |
|
Cycloxydim |
N(B) |
H |
S |
O |
3,900 |
||
Cycluron |
ISO |
H |
S |
O |
2,600 |
||
Cyometrinil |
N(B) |
H |
S |
O |
2,277 |
||
Cyromazine |
ISO |
L |
S |
O |
3,300 |
||
Caimuron |
ISO |
H |
S |
O |
+5,000 |
||
Dalapon |
N(A,B,F) |
H |
S |
O |
9,330 |
||
Daminozide |
ISO |
H |
S |
O |
8,400 |
||
Desmedipham |
ISO |
H |
S |
O |
+9,600 |
||
Diafenthiuron |
ISO |
AC |
S |
O |
2,068 |
||
Dichlobenil |
ISO |
H |
S |
O |
3,160 |
||
Dichlorfenidim |
N(U) |
See diuron |
|||||
Dichlofluanid |
ISO |
F |
S |
O |
+5,000 |
||
Dichloropicolinic acid |
See clopyralid |
||||||
Diclobutrazol |
ISO |
F |
T |
S |
O |
+4,000 |
|
Diclomezine |
ISO |
F |
S |
O |
+10,000 |
||
Dicloran |
N(B) |
F |
S |
O |
4,000 |
||
Diethatyl |
ISO |
H |
S |
O |
2,300 |
||
Diethofencarb |
ISO |
F |
S |
O |
+5,000 |
||
Difenoxuron |
ISO |
H |
S |
O |
+7,750 |
||
Diflubenzuron |
ISO |
L |
S |
O |
+4,640 |
DS 77 |
|
Diflufenican |
N(B) |
H |
S |
O |
+2,000 |
||
Dikegulac |
ISO |
PGR |
S |
O |
+10,000 |
||
Dimefuron |
ISO |
H |
S |
O |
+2,000 |
||
Dimethirimol |
ISO |
F |
S |
O |
2,350 |
||
Dimethomorph |
ISO |
F |
S |
O |
+5,000 |
||
Dimethyl phthalate |
C |
RP (insect) |
L |
O |
8,200 |
||
Dinitramine |
ISO |
H |
S |
O |
3,000 |
||
Diphenyl |
See biphenyl |
||||||
Dipropetryn |
ISO |
H |
T |
S |
O |
4,050 |
|
Dipropyl isocinchomerate |
C |
RP (fly) |
L |
O |
5,230 |
||
Disodium octaborate |
See borax |
||||||
Ditalmifos |
ISO |
F |
OP |
S |
O |
5,660 |
Irritant to skin; allergenic |
Dithiopyr |
ISO |
H |
O |
+5,000 |
|||
Diuron |
ISO |
H |
S |
O |
3,400 |
||
Dodemorph |
ISO |
H |
L |
O |
4,500 |
||
Eglinazine |
ISO |
H |
S |
O |
+10,000 |
||
Ethalfluralin |
ISO |
H |
S |
O |
+10,000 |
||
Ethephon |
N(A) |
PGR |
S |
O |
+4,000 |
||
Ethidimuron |
ISO |
H |
S |
O |
+5,000 |
||
Ethirimol |
ISO |
FST |
S |
O |
6,340 |
||
Ethofumesate |
ISO |
H |
S |
O |
+6,400 |
||
Etofenprox |
N(B) |
I |
S |
O |
+10,000 |
||
Fenarimol |
ISO |
F |
S |
O |
2,500 |
||
Fenbutatin oxide |
ISO |
MT |
OT |
S |
O |
2,630 |
EHC 15 |
Fenchlorazole |
ISO |
H |
S |
O |
+5,000 |
||
Fenclorim |
ISO |
H |
S |
O |
+5,000 |
||
Fenfuram |
ISO |
FST |
S |
O |
+10,000 |
||
Fenidim |
N(U) |
See fenuron |
|||||
Fenitropan |
ISO |
F |
S |
O |
3,230 |
||
Fenoxaprop-ethyl |
N(B) |
H |
S |
O |
2,350 |
||
Fenoxycarb |
ISO |
I |
C |
S |
O |
+10,000 |
|
Fenpiclonil |
ISO |
FST |
S |
O |
+5,000 |
||
Fenpropimorph |
ISO |
F |
oil |
O |
3,515 |
||
Fenuron |
ISO |
H |
S |
O |
6,400 |
||
Fenuron-TCA |
(ISO) |
H |
S |
O |
4,000 |
||
Ferbam |
ISO |
F |
TC |
S |
O |
+10,000 |
|
Flamprop-M |
ISO |
H |
S |
O |
+3,000 |
||
Fluazifop |
ISO |
H |
P |
L |
O |
3,330 |
|
Flubenzimine |
ISO |
AC |
S |
O |
3,000 |
||
Flucycloxuron |
ISO |
AC |
S |
O |
+5,000 |
||
Flufenoxuron |
ISO |
I |
S |
O |
+3,000 |
||
Flumetralin |
N(B) |
PGR |
S |
O |
+5,000 |
||
Flumetsulam |
ISO |
H |
S |
O |
+5,000 |
||
Fluometuron |
ISO |
H |
S |
O |
+8,000 |
||
Fluorodifen |
ISO |
H |
S |
O |
9,000 |
||
Fluoromide |
N(J) |
F |
S |
O |
+10,000 |
||
Flupropanate |
ISO |
H |
S |
O |
+10,000 |
||
Flurecol butyl |
See flurenol |
||||||
Flurenol |
ISO |
PGR |
S |
O |
+5,000 |
||
Fluridone |
ISO |
H |
S |
O |
+10,000 |
||
Flurochloridone |
ISO |
H |
S |
O |
4,000 |
||
Fluthiacet |
ISO |
H |
S |
O |
+5,000 |
||
Fluroxypyr |
N(B) |
H |
S |
O |
+5,000 |
||
Fluthiacet |
ISO |
H |
S |
O |
+5,000 |
||
Flutolanil |
ISO |
F |
S |
O |
+10,000 |
||
Tau-fluvalinate |
ISO |
I |
PY |
oil |
O |
+3,000 |
Skin and eye irritant |
Folpet |
ISO |
F |
S |
O |
+10,000 |
HSG 72 |
|
Fosamine |
ISO |
H |
S |
O |
2,400 |
||
Fosetyl |
N(B) |
F |
S |
O |
5,800 |
||
Furmecyclox |
N(B) |
FST |
S |
O |
3,780 |
||
Gibberellic acid |
N(B) |
PGR |
S |
O |
+10,000 |
||
Glyphosate |
ISO |
H |
S |
O |
4,230 |
EHC 159, DS 91 |
|
Glyphosine |
ISO |
H |
S |
O |
3,920 |
Continues on next page.
Table 6. Technical products not included in the WHO Classification and believed to be obsolete or discontinued for use as pesticides
Allyxycarb |
Dinex |
Methacarbate |
Table 7. List of gaseous or volatile fumigants not classified under the WHO Recommended Classification of Pesticides by Hazard
Acrylonitrile (EHC 28; HSG 1) |
Ethylene dichloride (EHC 176) |
Note: The WHO Classification does not set out any criteria for air concentrations on which classification could be based. Most of these compounds are of high hazard and recommended exposure limits for occupational exposure have been adopted by national authorities in many countries.
Source: WHO 1996.
The entries and abbrevations used in the tables’ various columns are explained here under the corresponding heading.
Name
The first column in the tables list the approved name of active ingredients. Trade names are not listed since there are many of these.
Status
The following abbreviations are used:
Main use
In most cases only a single use is given. This is only for identification purposes and does not exclude other uses. The following abbreviations are used:
Chemical type
A limited number of chemical types are shown in this column. Most have some significance in the sense that they may have a common antidote or may be confused in the nomenclature with other chemical types. For example, thiocarbamates are not cholinesterase inhibitors and do not have the same effects as carbamates. The following abbreviations are used:
These chemical classification are included only for convenience and do not represent a recommendation on the part of the WHO as to the way in which pesticides should be classified. It should, furthermore, be understood that some pesticides may fall into more than one type.
Chemical type is not shown where it is apparent from the name.
Physical state
This refers only to the technical compound. The following are used:
It may happen in a few cases that where the technical product is a solid, highly concentrated liquid formulations may need to be classified in a more hazardous class. In most cases, oils have been classified as liquids unless very viscous at ordinary temperatures.
Route
Oral route values are used unless the dermal route values place the compound in a hazardous class or the dermal values are significantly lower than the oral values, although in the same class. The following abbreviations are used:
LD50 (mg/kg)
The LD50 value is a statistical estimate of the number of mg of toxicant per kg of body weight required to kill 50% of a large population of test animals; the rat is used unless otherwise states. A single value is given: “c” preceding the value indicates that it is a value within a wider than usual range, adopted for classification purposes; “+” preceding the value indicates that the kill at the stated dose was less than 50% of the test animals.
The toxicity data for pyrethroids are highly variable according to isomer ratios, the vehicle for oral administration and the husbandry of the test animals. The variability is reflected in the prefix “c”. The single LD50 value now chosen for classification purposes is based on administration in corn oil and is much lower than that in aqueous solutions. This has resulted in considerable changes in the classification of some products and also underlines the need for classification by formulation if labelling is to reflect true hazard.
The figures in this column are not median values; rather, a safety margin is incorporated by choosing the lower confidence limit in most cases. Where a sex difference occurs in LD50 values, the value for the more sensitive sex is used. A number of classification adjustments have been made in respect of some pesticides and these are explained. A borderline case has been classified in the more or less hazardous class after consideration of its toxicology and use experience.
In table 5, a number of pesticides are listed as unlikely to present any acute hazard in normal use. The WHO Classification is open-ended but it is clear that there must be a point at which the acute hazard posed by the use of these compounds is so low as to be negligible provided that the necessary precautions are taken. For the purposes of this table, it has been assumed that this point is an oral LD50 of 2,000 mg/kg for solids and 3,000 mg/kg for liquids. However, it should not be overlooked that in formulations of these technical products, solvents or vehicles may present a greater hazard than the actual pesticide and therefore classification of a formulation in one of the higher hazard classes may be necessary.
Biological pesticides are not included in the WHO Classification because the methods of the safety testing of live biological agents are not appropriate to classification procedures applied to chemical compounds.
Remarks
Where the classification of a technical product has been adjusted, the basis for this is indicated in this column. Major irritant properties are noted; these do not affect classification. Where the name of a technical product is cross-referenced, the referenced product will be found in the same table. Abbreviations are used to indicate that a WHO/FAO Data Sheet (DS) or an issue of International Programme on Chemical Safety (IPCS) Environmental Health Criteria (EHC) Series or Health and Safety Guide contains further information on the product; the relevant issue numbers follow the abbreviations.
Table 4. List of technical products classified in Class III: "Slightly hazardous"
Name |
Status |
Main use |
Chemical type |
Physical state |
Route |
LD50 (mg/kg) |
Remarks |
Acephate |
ISO |
I |
OP |
S |
O |
945 |
|
Acetochlor |
ISO |
H |
L |
O |
2,950 |
||
Acifluorfen |
ISO |
H |
S |
O |
1,370 |
Strong irritant to eyes |
|
Allethrin |
ISO |
I |
PY |
oil |
O |
c685 |
EHC 87; HSG 24 |
Ametryn |
ISO |
H |
T |
S |
O |
1,110 |
|
Amitraz |
ISO |
AC |
S |
O |
800 |
||
Azamethiphos |
ISO |
I |
OP |
S |
O |
1,010 |
|
Azidithion |
N(F) |
See menazon |
|||||
Barban |
ISO |
H |
S |
O |
1,300 |
||
Bensultap |
ISO |
I |
S |
O |
1,100 |
||
Bentazone |
ISO |
H |
S |
O |
1,100 |
||
Benzoylprop-ethyl |
(ISO) |
H |
S |
O |
1,555 |
||
Benzthiazuron |
ISO |
H |
S |
O |
1,280 |
||
Bromofenoxim |
ISO |
H |
S |
O |
1,217 |
||
Bromophos |
ISO |
I |
OP |
S |
O |
c1,600 |
DS 76 |
Buthidazole |
ISO |
H |
S |
O |
1,480 |
||
Cacodylic acid |
See dimethylarsinic acid |
||||||
Carbofos |
N(U) |
See malathion |
|||||
Chlorfenac |
ISO |
H |
OC |
S |
O |
575 |
|
Chlorfenethol |
ISO |
AC |
OC |
S |
O |
930 |
|
Chlorfenson |
ISO |
AC |
OC |
S |
O |
c2,000 |
Irritant to skin |
Chlorinat |
N(U) |
See barban |
|||||
Chlormequat (chloride) |
ISO |
PGR |
S |
O |
670 |
||
Chloroacetic acid |
C |
H |
S |
O |
650 |
Irritant to skin and eyes; data refer to sodium salt |
|
Chlorobenzilate |
ISO |
AC |
OC |
S |
O |
700 |
|
Chlorocholine chloride |
C |
See chlormequat |
|||||
Chlorthiamid |
ISO |
H |
S |
O |
757 |
||
Cismethrin |
ISO |
Resmethrin is a mixture of isomers, the trans isomer (70-80%) being also known as bioresmethrin and the cis isomer (20-30%) as cismethrin. Bioresmethrin (see table 62.5) alone is of much lower toxicity (oral LD50 9,000 mg/kg) (DS 34) |
|||||
Citrex |
N(U) |
See dodine |
|||||
Clofop |
ISO |
H |
L |
O |
1,208 |
||
Copper hydroxide |
C |
F |
S |
O |
1,000 |
||
Copper oxychloride |
C |
F |
S |
O |
1,440 |
||
4-CPA |
ISO |
PGR |
S |
O |
850 |
||
Crufomate |
ISO |
I |
OP |
S |
O |
770 |
|
Cycloate |
ISO |
H |
TC |
L |
O |
+2,000 |
|
Cyhexatin |
ISO |
AC |
OT |
S |
O |
540 |
|
Cymoxanil |
ISO |
F |
S |
O |
1,196 |
||
Cyproconazole |
N(B) |
F |
S |
O |
1,020 |
||
Dazomet |
ISO |
F-S |
S |
O |
640 |
Irritant to skin and eyes |
|
2,4-DB |
N(B) |
H |
S |
O |
700 |
||
DCBN |
N(J) |
See chlorthiamid |
|||||
Deet |
See diethyltoluamide |
||||||
Dehydroacetic acid |
C |
F |
S |
O |
1,000 |
||
2,4-DES |
N(B,U) |
See disul |
|||||
Desmetryn |
ISO |
H |
T |
S |
O |
1,390 |
|
Diallyl dichloroacetamide |
See dichlormid |
||||||
Dicamba |
ISO |
H |
S |
O |
1,707 |
||
Dichlone |
ISO |
FST |
S |
O |
1,300 |
||
Dichlormid |
N(A) |
H |
L |
O |
2,080 |
||
Dichlorobenzene |
C |
FM |
S |
O |
500-5,000 |
Mixture of isomers |
|
Dichlorophen |
ISO |
F |
OC |
S |
O |
1,250 |
|
Dichlorprop |
ISO |
H |
S |
O |
800 |
||
Diclofop |
ISO |
H |
S |
O |
565 |
||
Dicofol |
ISO |
AC |
S |
O |
c690 |
DS 81 |
|
Dienochlor |
ISO |
AC |
S |
O |
3,160 |
Acutely toxic by inhalation; skin sensitizer |
|
Diethyltoluamide |
ISO |
RP (insect) |
L |
O |
c2,000 |
DS 80 |
|
Difenoconazole |
ISO |
F |
T |
S |
O |
1,453 |
|
Dimepiperate |
ISO |
H |
TC |
S |
O |
946 |
|
Dimethachlor |
ISO |
H |
S |
O |
1,600 |
||
Dimethametryn |
ISO |
H |
T |
L |
O |
3,000 |
|
Dimethipin |
ISO |
H |
S |
O |
1,180 |
||
Dimethylarsinic acid |
C |
H |
S |
O |
1,350 |
||
Diniconazole |
ISO |
F |
S |
O |
639 |
||
Dinocap |
ISO |
AC,F |
CNP |
S |
O |
980 |
|
Diphenamid |
ISO |
H |
S |
O |
970 |
||
Disul |
ISO |
H |
S |
O |
730 |
||
Dithianon |
ISO |
F |
S |
O |
640 |
||
2,4-DP |
N(U) |
See dichlorprop |
|||||
Dodine |
ISO |
F |
S |
O |
1,000 |
||
Doguadine |
N(F) |
See dodine |
|||||
DSMA |
See methylarsonic acid |
||||||
Empenthrin ((1R) isomers) |
ISO |
I |
PY |
oil |
O |
+2,280 |
|
Ephirsulphonate |
N(U) |
See chlorfenson |
|||||
Esprocarb |
ISO |
H |
TC |
L |
O |
+2,000 |
Skin and eye irritant |
Etacelasil |
ISO |
PGR |
L |
O |
2,065 |
||
Etaconazole |
ISO |
F |
S |
O |
1,340 |
||
Ethohexadiol |
N(A) |
RP (insect) |
L |
O |
2,400 |
||
Etridiazole |
ISO |
F |
L |
O |
2,000 |
||
Fenoprop |
ISO |
H |
S |
O |
650 |
||
Fenson |
ISO |
AC |
S |
O |
1,550 |
||
Fenothiocarb |
ISO |
L |
C |
S |
O |
1,150 |
|
Fenpropidin |
ISO |
F |
S |
O |
1,440 |
||
Fenthiaprop |
N(B) |
H |
S |
O |
915 |
||
Ferimzone |
ISO |
F |
S |
O |
725 |
||
Flamprop |
ISO |
H |
S |
O |
1,210 |
||
Fluchloralin |
ISO |
H |
S |
O |
1,550 |
||
Fluoroglycofen |
N(B) |
H |
S |
O |
1,500 |
||
Flurprimidol |
ISO |
PGR |
S |
O |
709 |
||
Flusilazole |
N(B) |
F |
S |
O |
1,110 |
||
Flutriafol |
ISO |
F,FST |
T |
S |
O |
1,140 |
|
Fomesafen |
ISO |
H |
OC |
S |
O |
1,250 |
|
Fuberidazole |
ISO |
F |
S |
O |
1,100 |
||
Furalaxyl |
ISO |
F |
S |
O |
940 |
||
Glufosinate |
ISO |
H |
S |
O |
1,625 |
||
Heptopargil |
ISO |
PGR |
L |
O |
2,100 |
||
Hexazinone |
ISO |
H |
S |
O |
1,690 |
||
Hydramethylnon |
N(A,B) |
I |
S |
O |
1,200 |
||
IBP |
See iprobenphos |
||||||
Iprobenphos |
N(B) |
F |
S |
O |
600 |
||
Isoprothiolane |
ISO |
F |
S |
O |
1,190 |
||
Isoproturon |
ISO |
H |
S |
O |
1,800 |
||
Isouron |
ISO |
H |
S |
O |
630 |
||
Isoxapyrifop |
ISO |
H |
S |
O |
500 |
||
Kelthane |
N(J) |
See dicofol |
|||||
Malathion |
ISO |
I |
OP |
L |
O |
c2,100 |
LD50 value can vary according to impurities. This value has been adopted for classification purposes and is that of a technical product conforming to WHO specifications; DS 29 |
Maldison |
N(Aus,NZ) |
See malathion |
|||||
MCPA |
ISO |
H |
S |
O |
700 |
||
MCPA-thioethyl |
ISO |
H |
S |
O |
790 |
||
MCPB |
ISO |
H |
S |
O |
680 |
||
Mecoprop |
ISO |
H |
S |
O |
930 |
||
Mecoprop-P |
ISO |
H |
S |
O |
1,050 |
||
Mefluidide |
ISO |
H |
S |
O |
1,920 |
||
Menazon |
ISO |
AP |
OP |
S |
O |
1,950 |
|
Mepiquat |
ISO |
PGR |
S |
O |
1,490 |
||
Metalaxyl |
ISO |
F |
S |
O |
670 |
||
Metaxon |
N(U) |
See MCPA |
|||||
Metconazole |
ISO |
F |
S |
O |
660 |
||
Methazole |
N(A,B) |
H |
S |
O |
4,543 |
Slightly irritant to eyes |
|
2-Methoxyethlymercury silicate |
C |
FST |
OM |
S |
O |
1,140 |
|
Methylarsonic acid |
ISO |
H |
S |
O |
1,800 |
||
Metolachlor |
ISO |
H |
L |
O |
2,780 |
||
MSMA |
See methylarsonic acid |
||||||
Myclobutanil |
N(B) |
F |
S |
O |
1,600 |
||
2-Napthyloxy acetic acid |
ISO |
PGR |
S |
O |
600 |
||
Nitrapyrin |
ISO |
B-S |
S |
O |
1,072 |
||
Nuarimol |
ISO |
F |
S |
O |
1,250 |
||
Octhilinone |
ISO |
F |
S |
O |
1,470 |
||
N-octyl bicycloheptene dicarboximide |
C |
SY |
L |
O |
2,800 |
||
Oxadixyl |
N(B) |
F |
S |
O |
1,860 |
||
Paclobutrazol |
ISO |
PGR |
S |
O |
1,300 |
||
Pallethrine |
N(F) |
See allethrin |
|||||
Para-dichlorobenzene |
See dichlorobenzene |
||||||
Pendimethalin |
ISO |
H |
S |
O |
1,050 |
||
Perfluidone |
ISO |
H |
S |
O |
920 |
||
Pimaricin |
N(B) |
F |
S |
O |
2,730 |
Antibiotic, identical with tennecetin and natamycin |
|
Piproctanyl |
ISO |
PGR |
S |
O |
820 |
||
Pirimiphos-methyl |
ISO |
I |
OP |
L |
O |
2,018 |
DS 49 |
Prochloraz |
ISO |
F |
S |
O |
1,600 |
||
Propachlor |
ISO |
H |
S |
O |
1,500 |
DS 78 |
|
Propanil |
ISO |
H |
S |
O |
c1,400 |
||
Propargite |
ISO |
AC |
L |
O |
2,200 |
||
Pyrazoxyfen |
ISO |
H |
S |
O |
1,644 |
||
Pyridaben |
ISO |
AC |
S |
O |
820 |
||
Pyridaphenthion |
N(J) |
I |
OP |
S |
O |
769 |
|
Pyridate |
ISO |
H |
S |
O |
c2,000 |
||
Pyrifenox |
ISO |
F |
L |
O |
2,900 |
||
Quinoclamine |
ISO |
H |
S |
O |
1,360 |
||
Quizalofop |
N(B) |
H |
S |
O |
1,670 |
||
Resmethrin |
ISO |
I |
PY |
S |
O |
2,000 |
See cismethrin; EHC 92, DS 83, HSG 25 |
Ryania |
C |
I |
S |
O |
c750 |
LD50 varies: vegetable product |
|
Sesamex |
N(A) |
SY |
L |
O |
2,000 |
||
Sethoxydim |
ISO |
H |
L |
O |
3,200 |
||
Silvex |
N(A) |
See fenoprop |
|||||
Simetryn |
ISO |
H |
T |
S |
O |
1,830 |
|
Sodium chlorate |
ISO |
H |
S |
O |
1,200 |
||
Sulfluramid |
ISO |
I |
S |
O |
543 |
||
Sulfoxide |
N(A) |
SY |
L |
O |
2,000 |
||
2,3,6-TBA |
ISO |
H |
S |
O |
1,500 |
||
Tebuthiuron |
ISO |
H |
S |
O |
644 |
||
Thiram |
ISO |
F |
S |
O |
560 |
DS 71 |
|
TMTD |
N(U) |
See thiram |
|||||
2,4,5-TP |
N(F,J,U) |
See fenoprop |
|||||
Tralkoxydim |
ISO |
H |
S |
O |
934 |
||
Triadimefon |
ISO |
F |
S |
O |
602 |
||
Triadimenol |
ISO |
FST |
S |
O |
900 |
||
Tri-allate |
ISO |
H |
TC |
L |
O |
2,165 |
HSG 89 |
Trichlorfon |
ISO |
H |
OP |
S |
O |
560 |
DS 27; EHC 132; HSG 66 |
Triclopyr |
ISO |
H |
S |
O |
710 |
||
Tridiphane |
N(B) |
H |
S |
O |
1,740 |
||
Trifenmorph |
ISO |
M |
S |
O |
1,400 |
DS 64 |
|
Triflumizole |
N(B) |
F |
S |
O |
695 |
||
Undecan-2-one |
C |
RP (dogs,cats) |
oil |
O |
2,500 |
||
Uniconazole |
ISO |
PGR |
S |
O |
1,790 |
||
XMC |
N(J) |
I |
C |
S |
O |
542 |
|
Ziram |
ISO |
F |
S |
O |
1,400 |
Irritant to skin; DS 73 |
Source: WHO 1996.
Adapted from WHO 1996.
Individual products are classified in a series of tables according to the products’ oral and dermal toxicity and physical states. Technical products classified as Class IA (extremely hazardous, Class IB (highly hazardous), Class II (moderately hazardous) and Class III (slightly hazardous) are listed in table 1, table 2, table 3 and table 4, respectively. Technical products unlikely to present any acute hazard in normal use are listed in table 5. The classification given in tables 1 to 5 is of technical compounds and only forms the starting point for the final classification of an actual formulation: the final classification of any product depends on its formulation. Classification of mixtures of pesticides is not included; many of these mixtures are marketed with varying concentrations of active constituents. (For information on how to find the hazard class of formulations and mixtures, see WHO 1996.) Technical products believed to be absolete or discontinued (see table 6) are not inclued in the Classification. Table 7 lists gaseous fumigants not included in the WHO Recommanded Classification of Pesticides by Hazard.C
On this page are the following tables. Please return to the Minerals and Agricultural Chemicals chapter page for the remaining tables.
Table 1. List of technical products classified in Class IA: "Extremely hazardous"
Table 2. List of technical products classified in Class IB: "Highly hazardous"
Table 3. List of technical products classified in Class II: "Moderately hazardous"
Table 1. List of technical products classified in Class IA: "Extremely hazardous"
Name |
Status |
Main use |
Chemical type |
Physical state |
Route |
LD50 (mg/kg) |
Remarks |
Acrolein |
C |
H |
L |
O |
29 |
EHC 127; HSG 67 |
|
Alachlor |
ISO |
H |
S |
O |
930 |
Adjusted classification; carcinogenic in rats and mice; DS 84 |
|
Aldicarb |
ISO |
I-S |
C |
S |
O |
0.93 |
DS 53; EHC 121; HSG 64 |
Arsenous oxide |
C |
R |
S |
O |
180 |
Adjusted classification; minimum lethal dose for humans of 2 mg/kg; evidence of carcinogenicity for humans is sufficient; EHC 18; HSG 70 |
|
Brodifacoum |
ISO |
R |
S |
O |
0.3 |
DS 57; EHC 175; HSG 93 |
|
Bromadialone |
ISO |
R |
S |
O |
1.12 |
DS 88; EHC 175; HSG 94 |
|
Bromethalin |
ISO |
R |
S |
O |
2 |
||
Calcium cyanide |
C |
FM |
S |
O |
39 |
Adjusted classification; calcium cyanide is in Class IA as it reacts with moisture to produce hydrogen cyanide gas; the gas is not classified under the WHO system (see table 7) |
|
Captafol |
ISO |
F |
S |
O |
5,000 |
Adjusted classification; carcinogenic in rats and mice; HSG 49 |
|
Chlorfenvinphos |
ISO |
I |
OP |
L |
O |
10 |
|
Chlormephos |
ISO |
I |
OP |
L |
O |
7 |
|
Chlorophacinone |
ISO |
R |
S |
O |
3.1 |
DS 62; EHC 175 |
|
Chlorthiophos |
ISO |
I |
OP |
L |
O |
9.1 |
|
Coumaphos |
ISO |
AC, MT |
OP |
L |
O |
7.1 |
|
CVP |
N(J) |
See chlorfenvinphos |
|||||
Cycloheximide |
ISO |
F |
S |
O |
2 |
||
DBCP |
N(J) |
See dibromochloropropane |
|||||
Demephion-O and -S |
ISO |
I |
OP |
L |
O |
15 |
|
Demeton-O and -S |
ISO |
I |
OP |
L |
O |
2.5 |
DS 60 |
Dibromochloropropane |
C |
F-S |
L |
O |
170 |
Adjusted classification; has been found to cause sterility in humans and is mutagenic and carcinogenic in animals |
|
Difenacoum |
ISO |
R |
S |
O |
1.8 |
EHC 175; HSG 95 |
|
Difethialone |
ISO |
R |
S |
O |
0.56 |
EHC 175 |
|
Difolatan |
N(J) |
See captafol |
|||||
Dimefox |
ISO |
I |
OP |
L |
O |
1 |
Volatile |
Diphacinone |
ISO |
R |
S |
O |
2.3 |
EHC 175 |
|
Disulfoton |
ISO |
I |
OP |
L |
O |
2.6 |
DS 68 |
EPN |
N(A,J) |
I |
OP |
S |
O |
14 |
Has been reported as causing delayed neurotoxicity in hens |
Ethoprop |
N(A) |
See ethoprophos |
|||||
Ethoprophos |
ISO |
I-S |
OP |
L |
D |
26 |
DS 70 |
Ethylthiometon |
N(J) |
See disulfoton |
|||||
Fenamiphos |
ISO |
N |
OP |
L |
O |
15 |
DS 92 |
Fensulfothion |
ISO |
I |
OP |
L |
O |
3.5 |
DS 44 |
Flocoumafen |
N(B) |
R |
S |
O |
0.25 |
EHC 175 |
|
Fonofos |
ISO |
I-S |
OP |
L |
O |
c8 |
|
Hexachlorobenzene |
ISO |
FST |
S |
D |
10,000 |
Adjusted classification; has caused a serious outbreak of porphyria in humans; DS 26 |
|
Leptophos |
ISO |
I |
OP |
S |
O |
50 |
Adjusted classification; has been shown to cause delayed neurotoxicity; DS 38 |
M74 |
N(J) |
See disulfoton |
|||||
MBCP |
N(J) |
See leptophos |
|||||
Mephosfolan |
ISO |
I |
OP |
L |
O |
9 |
|
Mercuric chloride |
ISO |
F-S |
S |
O |
1 |
||
Merkaptophos |
N(U) |
When mixed with merkaptophosteolovy, see demeton -O and -S |
|||||
Metaphos |
N(U) |
See parathion-methyl |
|||||
Mevinphos |
ISO |
I |
OP |
L |
D |
4 |
DS 14 |
Nitrofen |
ISO |
H |
S |
O |
c3,000 |
Adjusted classification; carcinogenic in rats and mice; teratogenic in several species tested; DS 84 |
|
Parathion |
ISO |
I |
OP |
L |
O |
13 |
DS 6; HSG 74 |
Parathion-methyl |
ISO |
I |
OP |
L |
O |
14 |
DS 7; EHC 145; HSG 75 |
Phenylmercury acetate |
ISO |
FST |
S |
O |
24 |
Adjusted classification; highly toxic to mammals and very small doses have produced renal lesions; teratogenic in the rat |
|
Phorate |
ISO |
I |
OP |
L |
O |
2 |
DS 75 |
Phosfolan |
ISO |
I |
OP |
L |
O |
9 |
|
Phosphamidon |
ISO |
I |
OP |
L |
O |
7 |
DS 74 |
Prothoate |
ISO |
AC,I |
OP |
L |
O |
8 |
|
Red squill |
See scilliroside |
||||||
Schradan |
ISO |
I |
OP |
L |
O |
9 |
|
Scilliroside |
C |
R |
S |
O |
c0.5 |
Induces vomiting in mammals |
|
Sodium fluoroacetate |
C |
R |
S |
O |
0.2 |
DS 16 |
|
Sulfotep |
ISO |
I |
OP |
L |
O |
5 |
|
TEPP |
ISO |
AC |
OP |
L |
O |
1.1 |
|
Terbufos |
ISO |
I-S |
OP |
L |
O |
c2 |
|
Thiofos |
N(U) |
See parathion |
|||||
Thionazin |
ISO |
N |
OP |
L |
O |
11 |
|
Timet |
N(U) |
See phorate |
Table 2. List of technical products classified in Class IB: "Highly hazardous"
Name |
Status |
Main use |
Chemical type |
Physical state |
Route |
LD50 (mg/kg) |
Remarks |
Aldoxycarb |
ISO |
I,N |
C |
S |
O |
27 |
|
Aldrin |
ISO |
I |
OC |
S |
D |
98 |
DS41; EHC 91; HSG 21 |
Allyl alcohol |
C |
H |
L |
O |
64 |
Highly irritant to skin and eyes |
|
Aminocarb |
ISO |
I |
C |
S |
O |
50 |
|
Antu |
ISO |
R |
S |
O |
8 |
Induces vomiting in dogs. Some impurities are carcinogenic |
|
Azinphos-ethyl |
ISO |
I |
OP |
S |
O |
12 |
DS 72 |
Azinphos-methyl |
ISO |
I |
OP |
S |
O |
16 |
DS 59 |
Benfuracarb |
N(B) |
I |
C |
L |
O |
138 |
|
Bis(tributyltin) oxide |
C |
F,M |
L |
O |
194 |
Irritant to skin. DS 65; EHC 15 |
|
Blasticidin-S |
N(J) |
F |
S |
O |
16 |
||
Bromophos-ethyl |
ISO |
I |
OP |
L |
O |
71 |
|
Butocarboxim |
ISO |
I |
C |
L |
O |
158 |
|
Butoxycarboxim |
ISO |
I |
C |
L |
D |
288 |
|
Cadusafos |
ISO |
N,I |
OP |
L |
O |
37 |
|
Calcium arsenate |
C |
I |
S |
O |
20 |
||
Carbofuran |
ISO |
I |
C |
S |
O |
8 |
DS 56 |
Carbophenothion |
ISO |
I |
OP |
L |
O |
32 |
|
3-chloro-1,2-propanediol |
C |
R |
L |
O |
112 |
In non-lethal dosage is a sterilant for male rats |
|
Coumachlor |
ISO |
R |
S |
D |
33 |
||
Coumatetralyl |
ISO |
R |
S |
O |
16 |
||
Crotoxyphos |
ISO |
I |
OP |
L |
O |
74 |
|
zeta-Cypermethrin |
ISO |
I |
PY |
L |
O |
c86 |
|
DDVF |
N(U) |
See dichlorvos |
|||||
DDVP |
N(J) |
See dichlorvos |
|||||
Delnav |
N(U) |
See dioxathion |
|||||
Demeton-S-methyl |
ISO |
I |
OP |
L |
O |
40 |
DS 61 |
Demeton-S-methylsulphon |
ISO |
I |
OP |
S |
O |
37 |
|
Dichlorvos |
ISO |
I |
OP |
L |
O |
56 |
Volatile, DS 2; EHC 79; HSG 18 |
Dicrotophos |
ISO |
I |
OP |
L |
O |
22 |
|
Dieldrin |
ISO |
I |
OC |
S |
O |
37 |
DS 17: EHC 91 |
Dimetilan |
N(A,B) |
I |
C |
S |
O |
47 |
|
Dinoseb |
ISO |
H |
CNP |
L |
O |
58 |
|
Dinoseb acetate |
ISO |
H |
CNP |
L |
O |
60 |
|
Dinoterb |
ISO |
H |
CNP |
S |
O |
25 |
|
Dioxathion |
ISO |
I |
OP |
L |
O |
23 |
|
DMTP |
N(J) |
See methidathion |
|||||
DNBP |
N(J) |
See dinoseb |
|||||
DNBPA |
N(J) |
See dinoseb acetate |
|||||
DNOC |
ISO |
I-S,H |
CNP |
S |
O |
25 |
|
EDDP |
N(J) |
See edifenfos |
|||||
Edifenphos |
ISO |
F |
OP |
L |
O |
150 |
|
Endrin |
ISO |
I |
OC |
S |
O |
7 |
DS 1; EHC 130; HSG 60 |
ESP |
N(J) |
I |
OP |
L |
O |
105 |
|
Famphur |
N(A) |
I |
OP |
S |
O |
48 |
|
Flucythrinate |
ISO |
I |
PY |
L |
O |
c67 |
Irritant to skin and eyes |
Fluoroacetamide |
C |
R |
S |
O |
13 |
||
Formetanate |
ISO |
AC |
C |
S |
O |
21 |
|
Fosmethilan |
ISO |
I |
OP |
S |
O |
49 |
Irritant to skin and eyes. |
Furathiocarb |
N(B) |
I-S |
C |
L |
O |
42 |
|
Heptenophos |
ISO |
I |
OP |
L |
O |
96 |
|
Isazofos |
ISO |
I-S |
OP |
L |
O |
60 |
|
Isofenphos |
ISO |
I |
OP |
oil |
O |
28 |
|
Isothioate |
ISO |
I |
OP |
L |
O |
150 |
|
Isoxathion |
ISO |
I |
OP |
L |
O |
112 |
|
Lead arsenate |
C |
L |
S |
O |
c10 |
||
Mecarbam |
ISO |
I |
C |
oil |
O |
36 |
|
Mercuric oxide |
ISO |
O |
S |
O |
18 |
||
Methamidophos |
ISO |
I |
OP |
L |
O |
30 |
HSG 79 |
Methidathion |
ISO |
I |
OP |
L |
O |
25 |
|
Methomyl |
ISO |
I |
C |
S |
O |
17 |
DS 55, EHC 178; HSG 97 |
Methyl-merkapto-phosteolovy |
N(U) |
See demeton-S-methyl |
|||||
Metilmerkapto-phosoksid |
N(U) |
See oxydemeton-methyl |
|||||
Metriltriazotion |
N(U) |
See azinphos-methyl |
|||||
Monocrotophos |
ISO |
I |
OP |
S |
O |
14 |
HSG 80 |
MPP |
N(J) |
See fenthion |
|||||
Nicotine |
ISO |
L |
D |
50 |
|||
Omethoate |
ISO |
I |
OP |
L |
O |
50 |
|
Oxamyl |
ISO |
I |
C |
S |
O |
6 |
DS 54 |
Oxydemeton-methyl |
ISO |
I |
OP |
L |
O |
65 |
|
Oxydeprofos |
N(B) |
See ESP |
|||||
Paris green |
C |
L |
S |
O |
22 |
Copper-arsenic complex |
|
Pentachlorophenol |
ISO |
I,F,H |
CNP |
S |
D |
80 |
Irritant to skin; EHC 71; HSG 19 |
Phenylmercury nitrate |
C |
FST |
OM |
S |
Oral LD50 not available, rat i.v. LD50 is 27 mg/kg |
||
Pirimiphos-ethyl |
ISO |
I |
OP |
L |
O |
140 |
|
Propaphos |
N(J) |
I |
OP |
L |
O |
70 |
|
Propetamphos |
ISO |
I |
OP |
L |
O |
106 |
|
Sodium arsenite |
C |
R |
S |
O |
10 |
||
Sodium cyanide |
C |
R |
S |
O |
6 |
||
Strychnine |
C |
R |
S |
O |
16 |
||
TBTO |
See bis-(tributyltin) oxide |
||||||
Tefluthrin |
N(B) |
I-S |
PY |
S |
O |
c22 |
|
Thallium sulfate |
C |
R |
S |
O |
11 |
DS 10 |
|
Thiofanox |
ISO |
I-S |
C |
S |
O |
8 |
|
Thiometon |
ISO |
I |
OP |
oil |
O |
120 |
DS 67 |
Thioxamyl |
See oxyamyl |
||||||
Triamiphos |
ISO |
F |
S |
O |
20 |
||
Triazophos |
ISO |
I |
OP |
L |
O |
82 |
|
Triazotion |
N(U) |
See azinphos-ethyl |
|||||
Vamidothion |
ISO |
I |
OP |
L |
O |
103 |
|
Warfarin |
ISO |
R |
S |
O |
10 |
DS 35, EHC 175; HSG 96 |
|
Zinc phosphide |
C |
R |
S |
O |
45 |
DS 24, EHC 73 |
Table 3. List of technical products classified in Class II: "Moderately hazardous"
Name |
Status |
Main Use |
Chemical type |
Physical state |
Route |
LD50 (mg/kg) |
Remarks |
Alanycarb |
ISO |
I |
C |
S |
O |
330 |
|
Allidochlor |
ISO |
H |
L |
O |
700 |
Irritant to skin and eyes |
|
Anilofos |
ISO |
H |
S |
O |
472 |
||
Azaconazole |
N(B) |
F |
S |
O |
308 |
||
Azocyclotin |
ISO |
AC |
OT |
S |
O |
80 |
|
Bendiocarb |
ISO |
I |
C |
S |
O |
55 |
DS 52 |
Bensulide |
ISO |
H |
L |
O |
270 |
||
Benzofos |
N(U) |
See phosalone |
|||||
BHC |
ISO |
See HCH |
|||||
gamma-BHC |
See gamma-HCH |
||||||
Bifenthrin |
N(B) |
I |
PY |
S |
O |
c55 |
|
Bilanafos |
ISO |
H |
S |
O |
268 |
||
Binapacryl |
ISO |
AC |
S |
O |
421 |
||
Bioallethrin |
C |
I |
PY |
L |
O |
c700 |
Bioallethrin, esbiothrin, esbiol and esdepalléthrine are members of the allethrin series; their toxicity varies considerably within this series according to concentrations of isomers. |
Bisthiosemi |
N(J) |
R |
S |
O |
c150 |
Induces vomiting in non-rodents |
|
BPMC |
See fenobucarb |
||||||
Bromoxynil |
ISO |
H |
S |
O |
190 |
||
Bronopol |
N(B) |
B |
S |
O |
254 |
||
Bufencarb |
ISO |
I |
C |
S |
O |
87 |
|
Butamifos |
ISO |
H |
L |
O |
630 |
||
Butenachlor |
ISO |
H |
L |
O |
1,630 |
||
Butylamine |
ISO |
F |
L |
O |
380 |
Irritant to skin |
|
Camphechlor |
ISO |
I |
OC |
S |
O |
80 |
DS 20; EHC 45 |
Carbaryl |
ISO |
I |
C |
S |
O |
c300 |
DS 3; EHC 153; HSG 78 |
Carbosulfan |
ISO |
I |
L |
O |
250 |
||
Cartap |
ISO |
I |
S |
O |
325 |
||
Chloralose |
C |
R |
S |
O |
400 |
||
Chlordane |
ISO |
I |
OC |
L |
O |
460 |
DS 36; EHC 34; HSG 13 |
Chlordimeform |
ISO |
AC |
OC |
S |
O |
340 |
|
Chlorphenamidine |
N(J) |
See chlordimeform |
|||||
Chlorphonium |
ISO |
PGR |
S |
O |
178 |
Irritant to skin and eyes |
|
Chlorpyrifos |
ISO |
I |
OP |
S |
O |
135 |
DS 18 |
Clomazone |
ISO |
H |
L |
O |
1,369 |
||
Copper sulfate |
C |
F |
S |
O |
300 |
||
Cuprous oxide |
C |
F |
S |
O |
470 |
||
Cyanazine |
ISO |
H |
T |
S |
O |
288 |
|
Cyanofenphos |
ISO |
I |
OP |
S |
O |
89 |
Has been reported as causing delayed neurotoxicity in hens; no longer manufactured |
Cyanophos |
ISO |
I |
OP |
L |
O |
610 |
|
CYAP |
N(J) |
See cyanophos |
|||||
Cyfluthrin |
ISO |
I |
PY |
S |
O |
c250 |
|
beta-Cyfluthrin |
ISO |
I |
PY |
S |
O |
450 |
|
Cyhalothrin |
ISO |
Ix |
PY |
oil |
O |
c144 |
EHC 99 |
lambda-Cyhalothrin |
N(B) |
I |
PY |
S |
O |
c56 |
EHC 142; HSG 38 |
CYP |
N(J) |
See cyanofenphos |
|||||
Cypermethrin |
ISO |
I |
PY |
S |
O |
c250 |
DS 58; EHC 82; HSG 22 |
alpha-Cypermethrin |
ISO |
I |
PY |
S |
O |
c79 |
EHC 142 |
beta-Cypermethrin |
ISO |
I |
PY |
S |
O |
166 |
|
Cyphenothrin ((1R)-isomers) |
ISO |
I |
PY |
L |
O |
318 |
|
Cyprofuram |
ISO |
F |
S |
O |
174 |
||
2,4-D |
ISO |
H |
PA |
S |
O |
375 |
DS 37; EHC 29; EHC 84 |
DAPA |
N(J) |
See fenaminosulf |
|||||
DDT |
ISO |
I |
OC |
S |
O |
113 |
DS 21; EHC 9; EHC 83 |
Deltamethrin |
ISO |
I |
PY |
S |
O |
c135 |
DS 50; EHC 97; HSG 30 |
Dialifor |
N(A,J) |
See dialifos |
|||||
Dialifos |
ISO |
I |
OP |
S |
D |
145 |
|
Di-allate |
ISO |
H |
TC |
L |
O |
395 |
|
Diazinon |
ISO |
I |
OP |
L |
O |
300 |
DS 45 |
Dibrom |
N (Denmark) |
See naled |
|||||
Dichlofenthion |
ISO |
I-S |
OP |
L |
O |
270 |
|
Difenzoquat |
ISO |
H |
S |
O |
470 |
||
Dimethoate |
ISO |
I |
OP |
S |
O |
c150 |
DS 42; EHC 90; HSG 20 |
Dinobuton |
ISO |
AC,F |
S |
O |
140 |
||
Dioxabenzophos |
N(B) |
I |
OP |
S |
O |
125 |
|
Dioxacarb |
ISO |
I |
C |
S |
O |
90 |
|
Diquat |
ISO |
H |
P |
S |
O |
231 |
Irritant to skin, and eyes, and damages nails; DS 40; EHC 39; HSG 52 |
Drazoxolon |
(ISO) |
FST |
S |
O |
126 |
||
ECP |
N(J) |
See dichlofenthion |
|||||
Endosulfan |
ISO |
I |
OC |
S |
O |
80 |
DS 15; EHC 40; HSG 17 |
Endothal-sodium |
(ISO) |
H |
S |
O |
51 |
||
EPBP |
N(J) |
I-S |
OP |
oil |
O |
275 |
|
EPTC |
ISO |
H |
TC |
L |
O |
1,652 |
|
Esbiol |
See bioallethrin |
||||||
Esbiothrin |
See bioallethrin |
||||||
Esdepalléthrine |
See bioallethrin |
||||||
Esfenvalerate |
ISO |
I |
PY |
S |
O |
87 |
|
Ethiofencarb |
ISO |
I |
C |
L |
O |
411 |
|
Ethion |
ISO |
I |
OP |
L |
O |
208 |
|
Etrimfos |
ISO |
I |
OP |
L |
O |
1,800 |
|
Fenaminosulf |
ISO |
F-S |
S |
O |
60 |
||
Fenazaquin |
ISO |
AC |
S |
O |
134 |
||
Fenchlorphos |
ISO |
I |
OP |
L |
O |
1,740 |
DS 69 |
Fenitrothion |
ISO |
I |
OP |
L |
O |
503 |
DS 30; EHC 133; HSG 65 |
Fenobucarb |
N(B) |
I |
C |
S |
O |
620 |
|
Fenpropathrin |
ISO |
I |
PY |
S |
O |
c66 |
|
Fenthion |
ISO |
I,L |
OP |
L |
D |
586 |
DS 23 |
Fentin acetate |
(ISO) |
F |
OT |
S |
O |
125 |
DS 22 |
Fentin hydroxide |
(ISO) |
F |
OT |
S |
O |
108 |
DS 22 |
Fenvalerate |
ISO |
I |
PY |
L |
O |
c450 |
EHC 95, DS 90; HSG 34 |
Fipronil |
N(B) |
I |
Pyrazole |
S |
O |
92 |
|
Fluvalinate |
N(B) |
I |
oil |
O |
282 |
Irritant to skin |
|
Fluxofenim |
ISO |
H |
oil |
O |
670 |
||
Formothion |
ISO |
I |
OP |
L |
O |
365 |
|
Fosfamid |
N(U) |
See dimethoate |
|||||
Furconazole-cis |
ISO |
F |
S |
O |
450 |
||
Guazatine |
N(B) |
FST |
S |
O |
230 |
LD50 value refers to triacetate |
|
Haloxyfop |
N(A,B) |
H |
S |
O |
393 |
||
HCH |
ISO |
I |
OC |
S |
O |
100 |
The LD50 varies according to the mixture of isomers. The value shown has been chosen, and the technical product placed in Class II, as a result of the cumulative properties of the beta isomer |
Gamma-HCH |
ISO |
I |
OC |
S |
O |
88 |
DS 12; EHC 124; HSG 54 |
Heptachlor |
ISO |
I |
OC |
S |
O |
100 |
DS 19; EHC 38; HSG 14 |
Imazalil |
ISO |
F |
S |
0 |
320 |
||
Imidacloprid |
N(B) |
I |
Nitro- guanidine |
S |
O |
450 |
|
Iminoctadine |
ISO |
F |
S |
O |
300 |
Eye irritant |
|
Ioxynil |
ISO |
H |
S |
O |
110 |
||
Ioxynil octanoate |
(ISO) |
H |
S |
O |
390 |
||
Isoprocarb |
ISO |
I |
C |
S |
O |
403 |
|
Karbation |
N(U) |
See metam-sodium |
|||||
Lindane |
ISO |
See gamma-HCH |
|||||
MEP |
N(J) |
See fenitrothion |
|||||
Mercaptodimethur |
See methiocarb |
||||||
Mercurous chloride |
C |
F |
S |
O |
210 |
||
Metaldehide |
ISO |
M |
S |
O |
227 |
||
Metam-sodium |
(ISO) |
F-S |
S |
O |
285 |
||
Methacrifos |
ISO |
I |
OP |
L |
O |
678 |
|
Methasulfocarb |
ISO |
F |
S |
O |
112 |
||
Methiocarb |
ISO |
I |
C |
S |
O |
100 |
|
Methyl isothiocyanate |
ISO |
F-S |
S |
O |
72 |
Skin and eye irritant |
|
Metolcarb |
ISO |
I |
C |
S |
O |
268 |
|
MICP |
N(J) |
See isoprocarb |
|||||
Molinate |
ISO |
H |
TC |
L |
O |
720 |
|
MPMC |
See xylylcarb |
||||||
Nabam |
ISO |
F |
TC |
S |
O |
395 |
Goitrogenic in rats |
NAC |
N(J) |
See carbaryl |
|||||
Naled |
ISO |
I |
OP |
L |
O |
430 |
DS 39 |
Norbormide |
ISO |
R |
S |
O |
52 |
||
2,4-PA |
N(J) |
See 2,4-D |
|||||
PAP |
N(J) |
See phenthoate |
|||||
Paraquat |
ISO |
H |
P |
S |
O |
150 |
Has serious delayed effects if absorbed; is relatively low hazard in actual use but is dangerous if accidentally taken orally; DS 4; EHC 39; HSG 51 |
Pebulate |
ISO |
H |
TC |
L |
O |
1,120 |
|
Permethrin |
ISO |
I |
PY |
L |
O |
c500 |
DS 51; EHC 94; HSG 33 |
PHC |
N(J) |
See propoxur |
|||||
Phenthoate |
ISO |
I |
OP |
L |
O |
c400 |
DS 48 |
Phosalone |
ISO |
I |
OP |
L |
O |
120 |
|
Phosmet |
ISO |
I,AC |
OP |
S |
O |
230 |
|
Phoxim |
ISO |
I |
OP |
L |
D |
1,975 |
DS 31 |
Phthalofos |
N(U) |
See phosmet |
|||||
Pindone |
ISO |
R |
S |
O |
50 |
||
Piperophos |
ISO |
H |
oil |
O |
324 |
||
Pirimicarb |
ISO |
AP |
C |
S |
O |
147 |
|
Polychlorcamphene |
N(U) |
See camphechlor |
|||||
Prallethrin |
ISO |
I |
PY |
oil |
O |
460 |
|
Profenofos |
ISO |
I |
OP |
L |
O |
358 |
|
Promacyl |
N(Aust) |
Ix |
C |
L |
O |
1,220 |
|
Promecarb |
ISO |
I |
C |
S |
O |
74 |
|
Propiconazole |
ISO |
F |
L |
O |
1,520 |
||
Propoxur |
ISO |
I |
C |
S |
O |
95 |
DS 25 |
Prosulfocarb |
ISO |
H |
L |
O |
1,820 |
||
Prothiofos |
ISO |
I |
OP |
L |
O |
925 |
|
Prothiophos |
See prothiofos |
||||||
Pyraclofos |
N(B) |
I |
OP |
L |
O |
237 |
|
Pyrazophos |
ISO |
F |
S |
O |
435 |
||
Pyrethrins |
C |
I |
L |
O |
500-1,000 |
Mixture of compounds present in Pyrethrum, Cineraefolium and other flowers; DS 11 |
|
Pyroquilon |
ISO |
F |
S |
O |
320 |
||
Quinalphos |
ISO |
I |
OP |
S |
O |
62 |
|
Quizalofop-p-tefuryl |
ISO |
H |
L |
O |
1,012 |
||
Reglon |
N(U) |
See diquat |
|||||
Ronnel |
N(A) |
See fenchlorphos |
|||||
Rotenone |
C |
I |
S |
O |
132-1,500 |
Compounds from roots of Derris and Lonchocarpus spp.; HSG 73 |
|
Salithion |
See dioxabenzofos |
||||||
SAP |
N(J) |
See bensulide |
|||||
Sec-butylamine |
See butylamine |
||||||
Sevin |
N(U) |
See carbaryl |
|||||
Sodium fluoride |
ISO |
I |
S |
O |
180 |
||
Sodium hexafluorosilicate |
ISO |
L-S |
S |
O |
125 |
||
Sulfallate |
ISO |
H |
oil |
0 |
850 |
Irritant to skin and eyes |
|
Sulprofos |
ISO |
I |
OP |
oil |
O |
130 |
|
2,4,5-T |
ISO |
H |
S |
O |
500 |
May contain a contaminant TCDD which affects toxicity: it should not exceed 0.01 mg/kg technical material; DS 13 |
|
TCA |
ISO |
The data shown refer to sodium trichloroacetic acid. In many countries, the term TCA refers to the free acid (now accepted by ISO); this is a solid with an oral LD50 of 400 mg/kg and if used as a pesticide is placed in Class II. It is highly corrosive to skin. |
|||||
Terbumeton |
ISO |
H |
T |
S |
O |
483 |
|
Tetraconazole |
ISO |
F |
oil |
O |
1,031 |
||
Thiazafluron |
ISO |
H |
S |
O |
278 |
||
Thiazfluron |
N(B) |
See thiazafluron |
|||||
Thicyofen |
ISO |
F |
S |
O |
368 |
||
Thiobencarb |
ISO |
H |
TC |
L |
O |
1,300 |
|
Thiocyclam |
ISO |
I |
S |
O |
310 |
||
Thiodan |
N(U) |
See endosulfan |
|||||
Thiodicarb |
ISO |
I |
S |
O |
66 |
||
Tolyl-methyl-carbamate |
See metolcarb |
||||||
Toxaphene |
N(A) |
See camphechlor |
|||||
Tralomethrin |
N(B) |
I |
PY |
S |
O |
c85 |
|
Trichloroacetic acid |
|||||||
Tricyclazole |
ISO |
F |
S |
O |
305 |
||
Tridemorph |
ISO |
F |
oil |
O |
650 |
||
Vernolate |
ISO |
H |
TC |
L |
O |
1,780 |
|
Xylylcarb |
N(B) |
I |
C |
S |
O |
380 |
Source: WHO 1996.
Kidney Cancer
Epidemiology
Historically, kidney cancer has been used to mean either all malignancies of the renal system (renal cell carcinoma (RCC), ICD-9 189.0; renal pelvis, ICD-9 189.1; and ureter, ICD-9 189.2) or RCC only. This categorization has led to some confusion in epidemiological studies, resulting in a need to scrutinize previously reported data. RCC comprises 75 to 80% of the total, with the remainder being primarily transitional cell carcinomas of the renal pelvis and ureter. Separation of these two cancer types is appropriate since the pathogenesis of RCC and of transitional cell carcinoma is quite different, and epidemiological risk factors are distinct as are the signs and symptoms of the two diseases. This section focuses on RCC.
The major identified risk factor for kidney cancer is tobacco smoking, followed by suspected but poorly defined occupational and environmental risk factors. It is estimated that the elimination of tobacco smoking would decrease the incidence of kidney cancer by 30 to 40% in industrialized countries, but occupational determinants of RCC are not well established. The population attributable risk due to occupational exposures has been estimated to be between zero, based on recognized carcinogenesis, and 21%, based on a multicentric multisite case-control study in the Montreal area of Canada. Early biomarkers of effect in association with biomarkers of exposure should assist in clarifying important risk factors. Several occupations and industries have been found in epidemiological studies to entail an increased risk of renal cancer. However, with the possible exception of agents used in dry cleaning and exposures in petroleum refining, the available evidence is not consistent. Statistical analysis of epidemiological exposure data in relation to biomarkers of susceptibility and effect will clarify additional aetiological causes.
Several epidemiological studies have associated specific industries, occupations and occupational exposures with increased risks of renal cell carcinoma. The pattern that emerges from these studies is not fully consistent. Oil refining, printing, dry cleaning and truck driving are examples of jobs associated with excess risk of kidney cancer. Farmers usually display decreased risk of RCC, but a Danish study linked long-term exposure to insecticides and herbicides with an almost fourfold excess of RCC risk. This finding requires confirmation in independent data, including specification of the possible causal nature of the association. Other products suspected of being associated with RCC include: various hydrocarbon derivatives and solvents; products of oil refining; petroleum, tar and pitch products; gasoline exhaust; jet fuel; jet and diesel engine emissions; arsenic compounds; cadmium; chromium (VI) compounds; inorganic lead compounds; and asbestos. Epidemiological studies have associated occupational gasoline vapour exposure with kidney cancer risk, some in a dose-response fashion, a phenomenon observed in the male rat for unleaded gasoline vapour exposure. These findings gain some potential weight, given the widespread human exposure to gasoline vapours in retail service stations and the recent increase in kidney cancer incidence. Gasoline is a complex mixture of hydrocarbons and additives, including benzene, which is a known human carcinogen.
The risk of kidney cancer is not consistently linked with social class, although increased risk has occasionally been associated with higher socio-economic status. However, in some populations a reverse gradient was observed, and in yet others, no clear pattern emerged. Possibly these variations may be related to lifestyle. Studies with migrant people show modification in RCC risk towards the level of the host country population, suggesting that environmental factors are important in the development of this malignancy.
Except for nephroblastoma (Wilms’ tumour), which is a childhood cancer, kidney cancer usually occurs after 40 years of age. An estimated 127,000 new cases of kidney cancer (including RCC and transitional cell carcinoma (TCC) of the renal pelvis and ureter), corresponding to 1.7% of the world total cancer incidence, occurred globally in 1985. The incidence of kidney cancer varies among populations. High rates have been reported for both men and women in North America, Europe, Australia and New Zealand; low rates in Melanesia, middle and eastern Africa and southeastern and eastern Asia. The incidence of kidney cancer has been increasing in most western countries, but stagnated in a few. Age-standardized incidence of kidney cancer in 1985 was highest in North America and western, northern and eastern Europe, and lowest in Africa, Asia (except in Japanese men) and the Pacific. Kidney cancer is more frequent in men than in women and ranks among the ten most frequent cancers in a number of countries.
Transitional cell carcinoma (TCC) of the renal pelvis is associated with similar aetiological agents as bladder cancer, including chronic infection, stones and phenacetin-containing analgesics. Balkan nephropathy, a slowly progressive, chronic and fatal nephropathy prevalent in the Balkan countries, is associated with high rates of tumours of the renal pelvis and ureter. The causes of Balkan nephropathy are unknown. Excessive exposure to ochratoxin A, which is considered possibly carcinogenic to humans, has been associated with the development of Balkan nephropathy, but the role of other nephrotoxic agents cannot be excluded. Ochratoxin A is a toxin produced by fungi which can be found in many food stuffs, particularly cereals and pork products.
Screening and diagnosis of kidney cancer
The sign and symptom pattern of RCC varies among patients, even up to the stage when metastasis appears. Because of the location of the kidneys and the mobility of contiguous organs to the expanding mass, these tumours are frequently very large at the time of clinical detection. Although haematuria is the primary symptom of RCC, bleeding occurs late compared to transitional cell tumours because of the intra-renal location of RCC. RCC has been considered the “medical doctor’s dream” but the “surgeon’s curse” because of the interesting constellation of symptoms related to paraneoplastic syndromes. Substances that increase the red blood cell count, calcium and factors which mimic abnormal adrenal gland function have been reported, and abdominal mass, weight loss, fatigue, pain, anaemia, abnormal liver function and hypertension have all been observed. Computerized axial tomography (CAT scan) of the abdomen and ultrasound are being ordered by physicians with increased frequency so, consequently, it is estimated that 20% of RCCs are diagnosed serendipitously as a result of evaluation for other medical problems.
Clinical evaluation of an RCC case consists of a physical examination to identify a flank mass, which occurs in 10% of patients. A kidney x ray with contrast may delineate a renal mass and the solid or cystic nature is usually clarified by ultrasound or CAT scan. The tumours are highly vascular and have a characteristic appearance when the artery is injected with radio-opaque contrast material. Arteriography is performed to embolize the tumour if it is very large or to define the arterial blood supply if a partial nephrectomy is anticipated. Fine-needle aspiration may be used to sample suspect RCC.
Localized RCC tumours are surgically removed with regional lymph nodes and, operatively, early ligation of the artery and vein is important. Symptomatically, the patient may be improved by removing large or bleeding tumours that have metastasized, but this does not improve survival. For metastatic tumours, localized pain control may be achieved with radiation therapy but the treatment of choice for metastatic disease is biological response modifiers (Interleukin-2 or α-interferon), although chemotherapy is occasionally used alone or in combination with other therapies.
Markers such as the cancer gene on chromosome 3 observed in cancer families and in von Hippel-Lindau disease may serve as biomarkers of susceptibility. Although tumour marker antigens have been reported for RCC, there is currently no way to detect these reliably in the urine or blood with adequate sensitivity and specificity. The low prevalence of this disease in the general population requires a high specificity and sensitivity test for early disease detection. Occupational cohorts at risk could potentially be screened with ultrasound. Evaluation of this tumour remains a challenge to the basic scientist, molecular epidemiologist and clinician alike.
Bladder Cancer
Epidemiology
More than 90% of bladder cancers in Europe and North America are transitional cell carcinomas (TCC). Squamous cell carcinoma and adenocarcinoma account for 5 and 1%, respectively, of bladder cancer in these regions. The distribution of histopathological types in bladder cancer is strikingly different in regions such as the Middle East and Africa where bladder cancer is associated with schistosomal infection. For instance, in Egypt, where schistosomiasis is endemic and bladder cancer is the major oncogenic problem, the most common type is squamous cell carcinoma, but the incidence of TCC is increasing with the rising prevalence of cigarette smoking. The discussion which follows focuses on TCC.
Bladder cancer continues to be a disease of significant importance. It accounted for about 3.5% of all malignancies in the world in 1980. In 1985, bladder cancer was estimated to be 11th in frequency on a global scale, being the eighth most frequent cancer among men, with an expected total of 243,000 new cases. There is a peak incidence in the seventh decade of life, and worldwide the male to female ratio is around three to one. Incidence has been increasing in almost all populations in Europe, particularly in men. In Denmark, where annual incidence rates are among the highest in the world, at 45 per 100,000 in men and 12 per 100,000 in women, the recent trend has been a further rise of 8 to 9% every 5 years. In Asia, the very high rates among the Chinese in Hong Kong have declined steadily, but in both sexes bladder cancer incidence is still much higher than elsewhere in Asia and more than twice as high as that among the Chinese in Shanghai or Singapore. Bladder cancer rates among the Chinese in Hawaii are also high.
Cigarette smoking is the single most important aetiological factor in bladder cancer, and occupational exposures rank second. It has been estimated that tobacco is responsible for one-third of all bladder cancer cases outside of regions where schistosomal infection is prevalent. The number of bladder cancer cases attributed in 1985 to tobacco smoking has been estimated at more than 75,000 worldwide, and may account for 50% of bladder cancer in western populations. The fact that all individuals who smoke similar amounts do not develop bladder cancer at the same rate suggests genetic factors are important in controlling the susceptibility. Two aromatic amines, 4-aminobiphenyl and 2-naphthylamine, are carcinogens associated with cigarette smoking; these are found in higher concentrations in “black tobacco” (air-cured) than in “blend tobacco” (flue-cured). Passive smoke increases the adducts in the blood and a dose-response of adduct formation has been correlated with increased risk of bladder cancer. Higher levels of adduct formation have been observed in cigarette smokers who are slow acetylators compared to fast acetylators, which suggests that genetically inherited acetylation status may be an important biomarker of susceptibility. The lower incidence of bladder cancer in Black compared to White races may be attributed to conjugation of carcinogenic metabolic intermediates by sulphotransferases that produce electrophiles. Detoxified phenolic sulphates may protect the urothelium. Liver sulphotransferase activity for N-hydroxyarylamines has been reported to be higher in Blacks than Whites. This may result in a decrease in the amount of free N-hydroxymetabolites to function as carcinogens.
Occupational bladder cancer is one of the earliest known and best documented occupational cancers. The first identified case of occupational bladder cancer appeared some 20 years after the inception of the synthetic dye industry in Germany. Numerous other occupations have been identified in the last 25 years as occupational bladder cancer risks. Occupational exposures may contribute to up to 20% of bladder cancers. Workers occupationally exposed include those working with coal-tar pitches, coal gasification and production of rubber, aluminium, auramine and magenta, as well as those working as hairdressers and barbers. Aromatic amines have been shown to cause bladder cancer in workers in many countries. Notable among this class of chemicals are 2-naphthylamine, benzidine, 4-nitrobiphenyl and 3,3r´-dichlorobenzidine. Two other aromatic amines, 4,4´-methylene dianiline (MDA) and 4,4´-methylene-bis-2-chloroaniline (MOCA) are among the most widely used of the suspected bladder carcinogens. Other carcinogens associated with industrial exposures are largely undetermined; however, aromatic amines are frequently present in the workplace.
Screening and diagnosis of bladder cancer
Screening for bladder cancer continues to receive attention in the quest to diagnose bladder cancer before it becomes symptomatic and, presumably, less amenable to curative treatment. Voided urine cytology and urinalysis for haematuria have been considered candidate screening tests. A pivotal question for screening is how to identify high-risk groups and then individuals within these groups. Epidemiological studies identify groups at risk while biomarkers potentially identify individuals within groups. In general, occupational screening for bladder cancer with haematuria testing and Papanicolaou cytology has been ineffective.
Improved detection of bladder cancer may be possible using the 14-day hemastick testing described by Messing and co-workers. A positive test was observed at least once in 84% of 31 patients with bladder cancer at least 2 months prior to the cystoscopic diagnosis of disease. This test suffers from a false-positive rate of 16 to 20% with half of these patients having no urological disease. The low cost may make this a useful test in a two-tier screen in combination with biomarkers and cytology (Waples and Messing 1992).
In a recent study, the DD23 monoclonal antibody using quantitative fluorescence image analysis detected bladder cancer in exfoliated uroepithelial cells. A sensitivity of 85% and specificity of 95% were achieved in a mixture of low- and high-grade transitional cell carcinomas including TaT1 tumours. The M344 tumour-associated antigen in conjunction with DNA ploidy had a sensitivity approaching 90%.
Recent studies indicate combining biomarkers with haematuria testing may be the best approach. A list of the applications of quantitative fluorescence urinary cytology in combination with biomarkers is summarized in Table 1. Genetic, biochemical and morphological early cell changes associated with premalignant conditions support the concept that individuals at risk can be identified years in advance of the development of overt malignancy. Biomarkers of susceptibility in combination with biomarkers of effect promise to detect individuals at risk with an even higher precision. These advances are made possible by new technologies capable of quantitating phenotypic and genotypic molecular changes at the single cell level thus identifying individuals at risk. Individual risk assessment facilitates stratified, cost-effective monitoring of selected groups for targeted chemoprevention.
Table 1. Applications of urinary cytology
Detection of CIS1 and bladder cancer
Monitoring surgical therapy:
Monitoring bladder following TURBT2
Monitoring upper urinary tract
Monitoring urethral remnant
Monitoring urinary diversion
Monitoring intravesical therapy
Selecting intravesical therapy
Monitoring effect of laser therapy
Evaluation of patients with haematuria
Establishing need for cystoscopy
Screening high-risk populations:
Occupational exposure groups
Drug abuse groups at risk for bladder cancer
Decision criteria for:
Cystectomy
Segmental ureteral resection versus nephroureterectomy
Other indications:
Detecting vesicoenteric fistula
Extraurological tumours invading the urinary tract
Defining effective chemopreventive agents
Monitoring effective chemotherapy
1 CIS, carcinoma in situ.
2 TURBT, transurethral resection for bladder tumour.
Source: Hemstreet et al. 1996.
Signs and symptoms of bladder cancer are similar to those of urinary tract infection and may include pain on urination, frequent voiding and blood and pus cells in the urine. Because symptoms of a urinary tract infection may herald a bladder tumour particularly when associated with gross haematuria in older patients, confirmation of the presence of bacteria and a keen awareness by the examining physician is needed. Any patient treated for a urinary tract infection which does not resolve immediately should be referred to a urology specialist for further evaluation.
Diagnostic evaluation of bladder cancer first requires an intravenous pyelogram (IVP) to exclude upper tract disease in the renal pelvis or ureters. Confirmation of bladder cancer requires looking in the bladder with a light (cystoscope) with multiple biopsies performed with a lighted instrument through the urethra to determine if the tumour is non-invasive (i.e., papillary or CIS) or invasive. Random biopsies of the bladder and prostatic urethra help to define field cancerization and field effect changes. Patients with non-invasive disease require close monitoring, as they are at risk of subsequent recurrences, although stage and grade progression are uncommon. Patients who present with bladder cancer that is already high-grade or invasive into the lamina propria are at equally high risk of recurrence but stage progression is much more likely. Thus, they usually receive intravesical instillation of immuno- or chemotherapeutic agents following transurethral resection. Patients with tumours invading the muscularis propria or beyond are much more likely to have metastasis already and can rarely be managed by conservative means. However, even when treated by total cystectomy (the standard therapy for muscle-invading bladder cancer), 20 to 60% eventually succumb to their disease, almost always due to metastasis. When regional or distal metastasis is present at diagnosis, the 5-year survival rates drop to 35 and 9%, respectively, despite aggressive treatment. Systemic chemotherapy for metastatic bladder cancer is improving with complete response rates reported at 30%. Recent studies suggest chemotherapy prior to cystectomy may improve survival in selected patients.
Bladder cancer staging is predictive of the biological potential for progression, metastasis, or recurrence in 70% of the cases. Staging of bladder cancer usually requires CAT scan to rule out liver metastasis, radioisotope bone scan to exclude spread to the bone, and chest x ray or CAT scan to exclude lung metastasis. A search continues for biomarkers in the tumour and the bladder cancer field that will predict which tumours will metastasize or recur. The accessibility of exfoliated bladder cells in voided specimens shows promise for using biomarkers for monitoring recurrence and for cancer prevention.
The renal and urinary systems are comprised of a complex series of organs which together function to filter wastes from the blood, and manufacture, store and discharge urine. These organ systems are vital to homeostasis through maintaining fluid balance, acid-base balance and blood pressure. The primary organs of the renal-urinary systems are the two kidneys and the urinary bladder. In the process of filtering waste products from the blood the kidneys are potentially exposed to high concentrations of endogenous and exogenous toxic substances. Thus, some kidney cells are exposed to concentrations a thousand times higher than in blood.
Problems that result in damage to the kidney may be pre-renal (affect blood supply to the kidney), renal (affect the kidney itself) or post-renal (affect any point along the path which the urine travels from the kidney to the end of the urethra or penis). Post-renal problems are usually obstructive in nature; a common site of obstruction is the prostate, juxtapositioned between the bladder and the urethra. Pre-existing disease of the prostate, bladder or ureters, particularly infection, obstruction or foreign bodies such as stones, can compromise kidney function and increase susceptibility to either acquired or genetic defects.
Understanding the microanatomy and molecular mechanisms of the kidneys and bladder is important to assessing susceptibility to, and monitoring and prevention of, occupational exposures. Toxicants seem to target specific parts of the kidney or bladder and result in the expression of specific biomarkers directly related to the damaged segment. Historically, predisposition to disease has been viewed from the epidemiological perspective of identifying a group of workers at risk. Today, with better understanding of the fundamental mechanisms of disease, individual risk assessment through the use of biomarkers of susceptibility, exposure, effect and disease is on the horizon. New ethical issues arise because of the pressure to develop cost-effective strategies to protect workers from occupational hazards. The pressure arises, in part, because genetic testing is gaining acceptance for evaluating disease predisposition and biomarkers of exposure and effect can serve as intermediate end-points at which intervention may be beneficial. The purpose of this chapter is to provide a medical review of the renal and urinary systems on the basis of which guidelines for assessing and reducing individual risk in the workplace could be set forth with due account taken of the ethical aspects involved.
Anatomy and Pathophysiology of the Kidney
The human kidney is a complex organ which functions to filter wastes from the blood through the production of urine. The two kidneys also perform a variety of other vital functions including maintaining homeostasis, regulating blood pressure, osmotic pressure and acid-base balance. The kidneys receive 25% of the total cardiac output of blood, potentially exposing them to endogenous and exogenous toxins.
The kidneys are located on each side of the spine in the lower portion of the back. Each weighs about 150 grams and is about the size of an orange. The kidney consists of three layers: the cortex (outer layer), the medulla and the renal pelvis. Blood flows into the cortex and medulla through the renal artery and branches into increasingly smaller arteries. Each of the arteries ends in a blood filtration unit called a nephron. A healthy kidney contains approximately 1.2 million nephrons, strategically positioned within the cortex and medulla.
A nephron consists of the glomerulus (a group of tiny blood vessels) surrounded by Bowman’s capsule (a two-layer membrane) that opens into a convoluted tubule. The fluid portion of blood, plasma, is forced through the glomerulus into Bowman’s capsule and then, as filtered plasma, passes into the convoluted tubule. About 99% of the water and essential nutrients that have been filtered are reabsorbed by the tubule cells and passed into the capillaries which surround the convoluted tubule. The unfiltered blood which remains in the glomerulus also flows into capillaries and returns through the renal vein to the heart.
The nephrons appear as long, looped ducts comprised of multiple segments each of which performs a variety of different functions designed to maintain the body’s homeostatic mechanisms. Figure 1 depicts a nephron and its orientation within the renal cortex and the medulla. Each nephron segment has a differential blood supply regulating the ionic gradient. Certain chemicals may directly affect specific segments of the nephron acutely or chronically depending on the type and dose of xenobiotic exposure. Depending on the segment of the microanatomy targeted, various aspects of kidney function may be affected.
Figure 1. Relationships of the vascular supply, the glomerulus and the tubular components of the nephron to each other and the orientation of these components within the renal cortex and medulla
Blood vessels to the kidney supply only the glomerular and tubular elements, delivering wastes to be filtered and absorbing nutrients, proteins and electrolytes in addition to supplying oxygen for organ viability. Ninety per cent of the blood flow is to the cortex, with a gradient decrease to the medulla. Such differential blood flow, and the positioning of the nephron units, are vital to the countercurrent mechanism which further concentrates the urine and potential nephrotoxins.
The glomerulus is positioned between the afferent and efferent arterioles. The efferent arterioles form a web of capillaries around each nephron unit with the exception of the distal tubule juxtaposition adjacent to the afferent blood supply of the glomerulus. Afferent and efferent tubules enervated by the sympathetic nerves respond to autonomic stimulation and hormonal mediators such as vasopression and antidiuretic hormone (ADH). An area called the macula densa, part of the juxtaglomerular apparatus, produces renin, a mediator of blood pressure, in response to osmotic changes and blood pressure. Renin is converted by liver enzymes to an octapeptide, angiotensin II, that regulates blood flow to the kidneys preferentially targeting the afferent arterioles and the mesangial cells of the glomerulus.
The glomerulus allows only certain size proteins with defined charge to pass through during filtration. Plasma filtration is controlled by a balance of osmotic and hydrostatic pressure. Specialized sugar molecules, glycosaminoglycans, provide negative anionic charge which inhibit, by electrostatic forces, the filtration of negatively charged materials. The three-cell layer of the glomerular basement membrane consists of multiple foot processes that increase the absorption area and create the pores through which the filtrate passes. Damage to the specialized basement membrane or the capillary endothelium may permit albumin, a type of protein, to be spilled in increased amounts into the urine. The presence of an excess amount of albumin or other micro-proteins in the urine serves as a marker of glomerular or tubular damage.
The renal interstitium is the space between the nephron units and is more prominent in the central medullary portion than in the outer cortex. Within the interstitium are interstitial cells that are in close proximity to the medullary blood vessels and tubule cells. With ageing there may be an increased prominence of interstitial cells in the cortex with associated fibrosis and scarring. The interstitial cells contain lipid droplets and may be involved in the control of blood pressure with the release of vascular relaxing or constricting factors. Chronic disease of the interstitium may affect the glomerulus and tubules, or conversely, disease of the glomerulus and tubules may affect the interstitium. Thus, in end-stage kidney disease it is sometimes difficult to precisely define the pathological mechanisms of renal failure.
The proximal collecting tubules absorb 80% of the sodium, water and chloride, and 100% of the urea. Each proximal tubule has three segments, with the last segment (P-3) the most vulnerable to xenobiotic (toxic foreign substance) exposures. When the proximal cells are damaged by heavy metals such as chromium, the concentrating ability of the kidney is impaired and urine may be more dilute. Toxicity to the P-3 segment results in the release into the urine of enzymes, such as intestinal alkaline phosphatase, N-acetyl-beta-D-glucosaminidase (NAG), or Tamm-Horsfall protein, which is associated with the brush-like border of the proximal tubule cells increasing the effective absorbing area.
Diagnosis and Testing for Nephrotoxicity
Serum creatinine is another substance filtered by the glomerulus but minimally absorbed by the proximal tubules. Damage to the glomerulus results in its inability to remove toxins produced by the body and there is an accumulation of serum creatinine. Because serum creatinine is a product of muscle metabolism and dependent on the patient’s body mass, it has low sensitivity and specificity for measuring renal function, but it is used frequently because it is convenient. A more sensitive and specific test is to quantitate the filtrate by measuring the creatinine (Cr) clearance; serum urinary creatinine clearance is calculated by the general formula CCr=UCr V/PCr, where UCrV is the amount of Cr excreted per unit time and PCr is the plasma concentration of the Cr. However, creatinine clearance is more complex, in terms of sampling for the test, and is thus impractical for occupational testing. Isotope clearance tests performed by radioactive labelling of compounds such as ortho-iodohippurate which are also cleared by the kidney are also effective, but not practical or cost-effective in the workplace setting. Differential function of individual kidneys may be determined using differential renal nuclear scans or selective catheterization of both kidneys by passage of a catheter from the bladder up through the ureter into the kidney. However these methods also are not readily employed for large-scale workplace testing. Because kidney function may be reduced by 70 to 80% prior to a detectable elevation in serum creatinine, and because other existing tests are either impractical or costly, non-invasive biomarkers are needed to detect low-dose acute intermittent exposures to the kidney. A number of biomarkers for detecting low-dose kidney damage or early changes associated with carcinogenesis are discussed in the section on biomarkers.
Although the proximal tubule cells absorb 80% of the fluids, the countercurrent mechanism and the distal collecting ducts fine-tune the amount of fluids absorbed by regulating ADH. ADH is released from the pituitary gland deep within the brain and responds to osmotic pressures and fluid volume. Exogenous compounds such as lithium may damage the distal collecting ducts and result in renal diabetes insipidus (passage of dilute urine). Inherited genetic disorders may also cause this defect. Xenobiotics normally affect both kidneys but complexities of interpretation arise when exposures are difficult to document or when there is pre-existing renal disease. Consequently, high-dose accidental exposures have served as markers for identifying nephrotoxic compounds in many instances. The majority of occupational exposures occur at low doses, and are masked by the reserve filtration and repair compensatory capability (hypertrophy) of the kidney. The challenge which remains is to detect low-dose exposures clinically undetected by current methods.
Anatomy and Pathophysiology of the Bladder
The urinary bladder is a hollow pouch in which urine is stored; normally, it contracts on demand for controlled emptying through the urethra. The bladder is located in the front, lower part of the pelvic cavity. The bladder is joined on either side to the two kidneys by muscular, peristaltic tubes, the ureters, which carry the urine from the kidneys to the bladder. The renal pelvis, ureters and bladder are lined with transitional epithelium. The outer layer of the urothelium consists of umbrella cells coated with a carbohydrate, glycosaminoglycan (GAG), layer. The transitional cells extend to the basement membrane of the bladder. The deep basal cells are thus protected by the umbrella cells but if the protective GAG layer is damaged the basal cells are susceptible to injury from urinary components. The microanatomy of the transitional epithelium allows it to expand and contract, and even with normal shedding of the umbrella cells the protective integrity of the basal cells is maintained.
The balanced neurological system that regulates storage and emptying may be damaged during electroshock or other trauma, such as spinal cord injury, occurring in the workplace. A major cause of death among quadraplegics is loss of bladder function resulting in chronic renal damage secondary to infection and stone formation. Chronic infection from incomplete emptying due to neurogenic or obstructive causes such as pelvic fracture or other trauma to the urethra and subsequent stricture formation is common. Persistent bacterial infection or stone formation that results in chronic inflammatory and malignant conditions of the bladder may be caused by reduced resistance (i.e., susceptibility) to exogenous exposures in the workplace.
Molecules associated with damage and repair within the bladder serve as potential intermediate end-point markers for both toxic and malignant conditions because many biochemical alterations occur during the changes related to cancer development. Like the kidney, bladder cells have active enzyme systems such as the cytochrome P-450 which may activate or inactivate xenobiotics. The functional activity of the enzymes is determined by genetic inheritance and exhibits genetic polymorphism. Voided urine contains cells exfoliated from the kidney, ureters, bladder, prostate and urethra. These cells provide targets, through the use of biomarkers, for evaluating changes in bladder and renal pathology. Remembering Virchow’s comment that all diseases start in the cells focuses our attention on the importance of cells, which are the molecular mirror of exposure episodes.
Environmental and Occupational Toxicology
A considerable volume of epidemiological data supports the causal relationship of occupational exposures in bladder cancer, but the precise contributions of workplace exposures to kidney failure and kidney cancer are difficult to estimate. In a recent report, it was estimated that up to 10% of end-stage renal disease could be attributed to workplace exposures, but results are difficult to validate because of changing environmental and chemical hazards, variations in diagnostic criteria and the often long latency period between exposure and disease. It is estimated that function of two-thirds of the nephrons of both kidneys may be lost before renal damage is clinically evident. However, evidence is mounting that what were previously thought to be socioeconomic or ethnic causes of nephrotoxicity may in fact be environmental, adding validity to the role of toxicants in disease development.
Nephrotoxicity may be directly related to the xenobiotic, or the xenobiotic may go through a single-step or multi-step activation or inactivation in the kidney or the liver. Activation of xenobiotics is regulated by complex sets of enzymes identified as Phase I, II and Ancillary. One Phase I enzyme is the P-450 oxidative system which acts through reduction or hydrolysis pathways. Phase II enzymes catalyse conjugation while ancillary enzymes regulate drug metabolism (Table 1 lists these enzymes). Various animal models have provided insight into metabolic mechanisms, and studies of kidney slices and microdissection of the kidney nephron units in tissue culture add insight into the pathological mechanisms. However, species and individual variables are considerable and, although mechanisms may be similar, caution is mandated in extrapolating results to humans in the workplace. The primary issues now are to determine which xenobiotics are nephrotoxic and/or carcinogenic, and to what target sites, and to develop methods to identify more accurately subclinical toxicity in the renal-urinary system.
Table 1. Drug-metabolism enzymes in kidney1
ENZYMES | ||
Phase I | Phase II | Ancillary |
Cytochrome P-450 | Esterase | GSH peroxides |
Microsomal FAD-containing mono-oxygenase | N-Acetyltransferase | GSSG reductase |
Alcohol and aldehyde dehydrogenases | GSH S-transferase | Superoxide dismutase |
Epoxide hydrolase | Thiol S-methyl-transferase | Catalase |
Prostaglandin synthase | UDP glucuronosyltransferase | DT-diaphorase |
Monoamine oxidase | Sulphotransferase | NADPH-generating pathways |
1 Phase I enzymes catalyse oxidation, reduction or hydrolysis.
Phase II enzymes generally catalyse conjugation.
Ancillary enzymes function in a secondary or supporting manner to facilitate drug metabolism.
Source: National Research Council 1995.
Non-malignant Renal-Urinary Disorders
Glomerulonephritis is an inflammatory reactive condition of the glomerular basement membrane or capillary endothelium. Acute and chronic forms of the disease are caused by a variety of infectious, autoimmune or inflammatory conditions or by exposure to toxic agents. Glomerulonephritis is associated with vasculitis, either systemic or limited to the kidney. Secondary chronic damage to the glomerulus also occurs during an intense cycle of assault from nephrotoxicity to the interstitium of the tubule cells. Epithelial glomerular crescents or proliferative forms are a hallmark of glomerulonephritis in kidney biopsy specimens. Blood, red blood cell (RBC) casts, or protein in the urine, and hypertension are symptoms of glomerulonephritis. A change in blood proteins may occur with lowering of certain fractions of the serum complement, a complex set of interacting proteins involved in the immune system, host defenses and clotting functions. Direct and indirect evidence supports the significance of xenobiotics as a causal factor of glomerulonephritis.
The glomerulus protects the oxygen-carrying red blood cells from passing through its filter. After centrifugation, normal urine contains only one RBC in 10 ml when viewed with high-power light microscopy. When RBCs leak through the glomerular filter and perhaps become individually dysmorphic, RBC casts that assume the cylindrical shape of the collecting nephrons form.
In support of the importance of toxins as an aetiological factor in glomerulonephritis, epidemiological studies reveal increased evidence of toxic exposures in patients who have undergone dialysis or who have been diagnosed with glomerulonephritis. Evidence of glomerular injury from acute hydrocarbon exposure is rare, but has been observed in epidemiological studies, with odds ratios ranging from 2.0 to 15.5. One example of acute toxicity is Goodpasture’s disease which results from hydrocarbon stimulation of antibody production to liver and lung proteins that cross-react with the basement membrane. Exacerbation of nephrotic syndrome, large amounts of protein in the urine, has also been observed in individuals re-exposed to organic solvents, while other studies reveal an historic relationship with a spectrum of renal disorders. Other solvents such as degreasing agents, paints and glues are implicated in more chronic forms of the disease. Awareness of the mechanisms of solvent excretion and reabsorption assists in identifying biomarkers because even minimal damage to the glomerulus results in increased leakage of RBCs into the urine. Although RBCs in the urine are a cardinal sign of glomerular injury, it is important to rule out other causes of haematuria.
Interstitial and tubular nephritis. As mentioned previously, the aetiology of chronic end-stage renal disease is frequently difficult to ascertain. It may be primarily glomerular, tubular or interstitial in origin and occur because of multiple acute episodes or chronic, low-dose processes. Chronic interstitial nephritis involves fibrosis and tubular atrophy. In its acute form, the disease is expressed by marked inflammatory infiltrate with accompanying fluid collection in the interstitial spaces. Interstitial nephritis may involve primarily the interstitium, or be manifest as a secondary event from chronic tubular injury, or it may result from post-renal causes such as obstruction. Prostaglandin-A synthase, an enzyme, is found primarily in the interstitium and is associated with the endoplasmic reticulum, a part of the protein machinery of the cell. Certain xenobiotics, such as benzidine and nitrofuranes, are reducing co-substrates for prostaglandin synthase and are toxic to the tubular interstitium.
Tubular and interstitial injury may occur from exposure to cadmium, lead or a variety of organic solvents. Most of the exposures are chronic, low-dose and toxicity is masked by the renal function reserve and the ability of the kidney to recover some functions. Interstitial nephritis may also result from vascular injury as caused, for example, by chronic carbon monoxide exposure. Proximal tubule cells are the most vulnerable to toxic substances in the blood because of intense exposure to toxins which filter through the glomerulus, internal enzyme systems that activate toxicants and the selective transport of toxicants. The epithelium in the various segments of the proximal tubule has slightly different qualities of lysosomal peroxidase enzymes and other compounds of genetic machinery. Thus, chromium exposure may result in both interstitial and tubular injury. Damage to the collecting tubules may occur when specific enzymes activate various xenobiotics such as chloroform, acetaminophen and p-aminophenol, and antibiotics such as Loradine. A secondary result of damage to the collecting ducts is the inability of the kidney to acidify the urine and the subsequent development of a metabolic acid state.
Nephrogenic diabetes insipidus, the condition in which urine becomes dilute, may be genetic or acquired. The genetic form involves mutations of the ADH receptors which are located on the basal lateral membrane of the collecting ducts, in the descending loop of Henle. ADH fine-tunes the reabsorption of water and certain ions such as potassium. Acquired diabetes insipidus may involve the tubule cells or the associated interstitium, both of which may be diseased because of a variety of conditions. Nephrogenic diabetes insipidus may accompany end-stage renal disease because of diffuse involvement of the interstitium. Consequently, the interstitium is unable to maintain a hypertonic environment for passive water movement from the tubular collecting ducts. Conditions which may cause diffuse interstitial changes are pyelonephritis, sickle cell anaemia and obstructive uropathy. The possible association of these conditions in relation to occupational exposure is an increased susceptibility of the kidney to xenobiotics. A limited number of nephrotoxic compounds have been identified that especially target the collecting tubule cells. Frequency, nocturia (more frequent voiding at night) and polydipsia (chronic thirst) are symptoms of nephrogenic diabetes insipidus. Movement of fluids through the collecting duct cells results in channels that form in response to ADH, affecting the microtubular function of the cells; consequently, drugs such as colchicine may affect the ADH. Two drugs which appear to act by slightly different mechanisms to correct ADH are hydrochlorothiazide and indomethacin, a prostaglandin synthase inhibitor.
Lithium-induced diabetes insipidus correlates with the duration of lithium therapy, average serum lithium level and total lithium carbonate dose. Interestingly, lithium concentrates in the collecting ducts and affects cyclic AMP, part of the energy metabolic pump pathway. Exposure to other compounds such as methoxyflurane and demeclocycline, the latter of which is used for the treatment of acne, also results in nephrogenic diabetes insipidus through an alternative pathway rendering the epithelial cells unresponsive to ADH.
Hypertension, or elevated blood pressure, the second most common cause of end-stage renal disease, is associated with multiple aetiological pathways. Hypertension can be caused by diabetic nephropathy, obstructive nephropathy, glomerulonephritis, polycystic kidney disease, pyelonephritis and vasculitis, and many of those diseases are associated with exposure to toxic compounds. A limited number of occupational exposures are directly associated with hypertension. One is lead, which causes renal vascular ischaemia and injury. The mechanism for lead-induced hypertension is probably regulated through the juxtaglomerular apparatus, the release of renin and the cleavage of renin by liver enzymes to angiotensin II. Drugs implicated in hypertension include amphetamines, oestrogens and oral contraceptives, steroids, cis-platinum, alcohol and tricyclic antidepressants. Hypertension may be gradual in onset or acute and malignant in nature. Malignant hypertension in which diastolic pressure is greater than 110 mm Hg is associated with nausea, vomiting and severe headache, and constitutes a medical emergency. Numerous drugs are available for the treatment of hypertension but over-treatment may result in decreased renal perfusion and a further loss of renal function. Whenever possible, withdrawal of the nephrotoxicant is the treatment of choice.
Differential diagnosis of haematuria and proteinuria
Haematuria (RBCs in the urine) and pyuria (white blood cells in the urine) are primary symptoms of many diseases of the renal-urinary system, and for categorical purposes may be considered non-specific cellular biomarkers. Because of their importance they are discussed separately here. A challenge to the occupational practitioner is to determine if haematuria signifies a permanent underlying medical condition that may be potentially life threatening or if it is attributable to occupational exposures. Clinical assessment of haematuria requires standardization and determination of whether it is pre-renal, renal or post-renal in origin.
Haematuria may be derived from lesions in the kidney per se or anywhere along the pathway of voided urine. Sites of origin include the kidney, collecting renal pelvis, ureters, bladder, prostate and urethra. Because of the serious diseases associated with haematuria, a single episode warrants a medical or urological evaluation. Greater than one RBC per high-power field can be a signal of disease, but significant haematuria may be missed on microscopic analysis in the presence of hypotonic (dilute) urine which may lyse RBCs. Pseudo-haematuria may be caused by beets, berries, vegetable dyes and concentrated urates. Initial haematuria suggests a urethral origin, terminal haematuria is usually prostatic in origin, and blood throughout voiding is from the bladder, kidney or ureter. Gross haematuria is associated with bladder tumours in 21% of the cases, but microscopic haematuria is much less frequently associated (2.2 to 12.5%).
Finding dysmorphic cells when haematuria is quantitatively assessed suggests an upper tract origin, particularly when associated with red blood cell casts. Understanding haematuria in relation to proteinuria provides additional information. The glomerular filtration device almost completely excludes proteins of a molecular weight greater than 250,000 Daltons, while low molecular weight proteins are freely filtered and absorbed normally by the tubule cells. The presence of high molecular weight proteins in the urine suggests lower tract bleeding while low molecular weight proteins are associated with tubular injury. Evaluation of the ratio of α-microglobulin to albumin and α-macroglobulin to albumin helps delineate glomerular from tubular interstitial nephropathy and lower tract bleeding potentially associated with urothelial neoplasia and other post-renal causes such as urinary tract infections.
A special diagnostic problem arises when two or more disease processes that cause the same symptoms are present concurrently. For example, haematuria is seen in both urothelial neoplasia and urinary tract infections. In a patient with both diseases, if the infection is treated and resolved, the cancer would remain. Therefore, it is important to identify the true cause of the symptoms. Haematuria is present in 13% of screened populations; approximately 20% of individuals have significant renal or bladder disorders and 10% of those will go on to develop genitourinary malignancy. Consequently, haematuria is an important biomarker of disease that must be appropriately evaluated.
Clinical interpretation of haematuria is enhanced by a knowledge of the patient’s age and sex, as indicated in Table 2 which shows causes of haematuria relative to the age and sex of the patient. Other causes of haematuria include renal vein thrombosis, hypercalcuria and vasculitis, as well as trauma such as jogging or other sports, and occupational events or exposures. Clinical evaluation of haematuria requires an x ray of the kidney, intravenous pyelogram (IVP), to rule out upper tract diseases including kidney stones and tumours, and a cystoscopy (looking into the bladder through a lighted instrument) to exclude bladder, prostate or urothelial cancers. Subtle vaginal causes must be excluded in women. Regardless of a patient’s age, a clinical evaluation is indicated if haematuria occurs and, depending on the identified aetiology, sequential follow-up evaluations may be indicated.
Table 2. The most common causes of haematuria, by age and sex
0–20 Years | 40–60 Years (females) |
Acute glomerulonephritis Acute urinary tract infection Congenital urinary tract anomalies with obstruction |
Acute urinary tract infection Stones Bladder tumour |
20–40 Years | 60+Years (males) |
Acute urinary tract infection Stones Bladder tumour |
Benign prostatic hyperplasia Bladder tumour Acute urinary tract infection |
40–60 Years (males) | 60+Years (females) |
Bladder tumour Stones Acute urinary tract infection |
Bladder tumours Acute urinary tract infection |
Source: Wyker 1991.
The use of recently identified biomarkers in conjunction with conventional cytology for evaluation of haematuria helps to assure that no occult or incipient malignancy is missed (see next section on biomarkers). For the occupational specialist, determining whether haematuria is a result of toxic exposure or occult malignancy is important. Knowledge of exposure and the patient’s age are critical parameters for making an informed clinical management decision. A recent study has demonstrated that together haematuria and biomarker analysis on exfoliated urinary cells from the bladder were the two best markers for detecting premalignant bladder lesions. Haematuria is observed in all cases of glomerular injury, in only 60% of patients with bladder cancer and in only 15% of patients with malignancies of the kidney itself. Thus, haematuria remains a cardinal symptom of renal and post-renal disease, but the final diagnosis may be complex.
Tests for nephrotoxicity: biomarkers
Historically, monitoring of toxins in the work environment has been the primary method of identifying risk. However, not all toxicants are known and, therefore, cannot be monitored. Also, susceptibility is a factor in whether xenobiotics will affect individuals.
Figure 2. Categories of biomarkers.
Biomarkers provide new opportunities for defining individual risk. For descriptive purposes and to provide a framework for interpretation, biomarkers have been classified according to the schema depicted in Figure 2. As in other diseases, biomarkers of nephrotoxicity and genitourinary toxicity may be related to susceptibility, exposure, effect or disease. Biomarkers may be genotypic or phenotypic, and may be functional, cellular or soluble in urine, blood or other body fluids. Examples of soluble markers are proteins, enzymes, cytokines and growth factors. Biomarkers may be assayed as the gene, message or protein product. These variable systems add to the complexity of biomarker evaluation and selection. One advantage of assaying the protein is that it is the functional molecule. The gene may not be transcribed and the quantity of message may not correspond to the protein product. A list of criteria for biomarker selection is shown in Table 3.
Table 3. Criteria for biomarker selection
Clinical utility | Assay considerations |
Strong biomarker | Stability of reagent |
Sensitivity | Cost of reagent |
Specificity | Fixation requirements |
Negative predictive value | Reproducibility of the assay |
Positive predictive value | Machine sensible parameters |
Functional role | Contribution to biomarker profile |
Sequence in oncogenesis | Adaptability to automation |
Source: Hemstreet et al. 1996.
The international scientific commitment to map the human genome made possible by advances in molecular biology established the basis for identifying biomarkers of susceptibility. Most instances of human disease, especially those resulting from environmental exposure to toxicants, involve a constellation of genes reflecting marked genetic diversity (genetic polymorphism). An example of such a gene product, as mentioned previously, is the P-450 oxidative enzyme system which may metabolize xenobiotics in the liver, kidney or bladder. Susceptibility factors may also control the basic mechanism for DNA repair, influence the susceptibility of various signalling pathways important to tumourigenesis (i.e., growth factors) or be related to inherited conditions that predispose to disease. An important example of an inherited susceptibility factor is the slow or fast acetylation phenotype that regulates the acetylation and inactivation of certain aromatic amines known to cause bladder cancer. Biomarkers of susceptibility may include not only genes that regulate the activation of xenobiotics but also proto-oncogenes and suppressor-oncogenes. The control of tumour cell growth involves a number of complex, interacting systems. These include a balance of positive (proto) oncogenes and negative (suppressor) oncogenes. Proto-oncogenes control normal cell growth and development, while suppressor-oncogenes control normal cellular division and differentiation. Other genes may contribute to pre-existing conditions such as a propensity to renal failure triggered by underlying conditions such as polycystic kidney disease.
A biomarker of exposure may be the xenobiotic itself, the metabolic metabolite or markers such as DNA adducts. In some instances the biomarker may be bound to a protein. Biomarkers of exposure may also be biomarkers of effect, if the effect is transient. If a biomarker of effect persists, it may become a biomarker of disease. Useful biomarkers of effect have a high association with a toxicant and are indicative of exposure. For disease detection, expression of the biomarker in close sequence to the onset of disease will have the highest specificity. The expected sensitivity and specificity of a biomarker depends on the risk versus benefit of the intervention. For instance, a biomarker such as F-actin, a cytoskeletal protein differentiation marker, that appears altered in early carcinogenesis may have a poor specificity for detection of pre-cancerous states because not all individuals with an abnormal marker will progress to disease. It may, however, be useful for selecting individuals and monitoring them while undergoing chemoprevention, provided the therapy is non-toxic. Understanding the time-frame and functional linkage between individual biomarkers is extremely important to individual risk assessment and to comprehending the mechanisms of carcinogenesis and nephrotoxicity.
Biomarkers of nephrotoxicity
Biomarkers of nephrotoxicity may be related to the aetiology of kidney failure (i.e., pre-renal, renal or post-renal) and the mechanisms involved in the pathogenesis of the process. This process includes cellular damage and repair. Toxic injury can affect the cells, glomerulus, interstitium or tubules with release of corresponding biomarkers. Xenobiotics may affect more than one compartment or may cause biomarker changes because of the interdependence of cells within the compartment. Inflammatory changes, autoimmune processes and immunological processes further promote the release of biomarkers. Xenobiotics may target one compartment in some circumstances and another under different conditions. One example is mercury which is, acutely, nephrotoxic to the proximal tubule while chronically it affects the arterioles. Response to injury can be divided into several major categories including hypertrophy, proliferation, degeneration (necrosis and apoptosis, or programmed cell death) and membrane alterations.
The majority of susceptibility factors are related to non-xenobiotic-associated renal disease. However, 10% of renal failure cases are attributed to environmental exposures to toxic compounds or iatrogenic induction by various compounds, such as antibiotics, or procedures such as administration of kidney x-ray contrast to a diabetic. In the workplace, identifying subclinical renal failure prior to potential additional nephrotoxic stress has potential practical utility. If a compound is suspected to be xenobiotic and it results in an effect specifically in the causal pathway of disease, intervention to reverse the effect is a possibility. Thus, biomarkers of effect eliminate many of the problems of calculating exposure and defining individual susceptibility. Statistical analysis of biomarkers of effect in relation to biomarkers of susceptibility and exposure should improve marker specificity. The more specific the biomarker of effect the less the requirement for a large sample size required for scientifically identifying potential toxins.
Biomarkers of effect are the most important class of markers and link exposure to susceptibility and disease. We have previously addressed the combining of cellular and soluble biomarkers to differentiate between haematuria originating in the upper tract or the lower tract. A list of soluble biomarkers potentially related to cellular nephrotoxicity is shown in Table 4. To date, none of these alone or as multiple biomarker panels detects subclinical toxicity with adequate sensitivity. Some problems with using soluble biomarkers are lack of specificity, enzyme instability, the dilutional effect of urine, variations in renal function, and non-specific protein interactions that may cloud the specificity of analysis.
Table 4. Potential biomarkers linked to cell injury
Immunological factors: -Humoral-antibodies and antibody fragments; components of complement cascade, and coagulation factors -Cellular-lymphocytes, mononuclear phagocytes, and other marrow- derived effectors (oesinophils, basophils, neutrophils and platelets) Lymphokines Major histocompatibility antigens Growth factors and cytokines: platelet- derived growth factor, epidermal growth factor, transforming growth factor (TGF), tumour-necrosis factor, interleukin-1, etc. Lipid mediators: prostaglandins Endothelin |
Extracellular-matrix components: -Collagens -Procollagen -Laminin -Fibronectin Reactive oxygen and nitrogen species Transcription factors and proto-oncogenes: c-myc, c-fos, c-jun, c-Haras, c-Ki-ras, and Egr-1 Heat shock proteins |
Source: Finn, Hemstreet et al. in National Research Council 1995.
One soluble growth factor with potential clinical application is urinary epidermal growth factor (EGF) which may be excreted by the kidney and is also altered in patients with transitional cell carcinoma of the bladder. Quantitation of urinary enzymes has been investigated but the usefulness of this has been limited by the inability to determine the origin of the enzyme and lack of assay reproducibility. The use of urinary enzymes and their widespread acceptance has been slow because of the restrictive criteria mentioned previously. Enzymes evaluated include alaminopeptidase, NAG and intestinal alkaline phosphatase. NAG is perhaps the most widely accepted marker for monitoring proximal tubule cell injury because of its localization in the S3 segment of the tubule. Because the precise cell of origin and pathological cause of urinary enzyme activity are unknown, interpretation of results is difficult. Furthermore, drugs, diagnostic procedures and co-existing diseases such as myocardial infarction may cloud the interpretation.
An alternative approach is to use monoclonal antibody biomarkers to identify and quantitate tubular cells in urine from various areas of the nephron segment. The utility of this approach will depend on maintaining the integrity of the cell for quantification. This requires appropriate fixation and sample handling. Monoclonal antibodies are now available which target specific tubule cells and distinguish, for example, proximal tubule cells from distal tubule cells or convoluted tubule cells. Transmission microscopy cannot effectively resolve differences between leukocytes and various types of tubule cells in contrast to electron microscopy which has been effective in detecting transplant rejection. Techniques such as high-speed quantitative fluorescence image analysis of tubular cells stained with monoclonal antibodies should solve this problem. In the near future, it should be possible to detect subclinical nephrotoxicity with a high degree of certainty as exposure occurs.
Biomarkers of malignant disease
Solid cancers arise in many cases from a field of biochemically altered cells which may or may not be histologically or cytologically altered. Technologies such as quantitative fluorescence image analysis capable of detecting biomarkers associated with premalignant conditions with certainty provide the horizon for targeted chemoprevention. Biochemical alterations may occur in a varied or ordered process. Phenotypically, these changes are expressed by a gradual morphological progression from atypia to dysplasia and finally to overt malignancy. Knowledge of the “functional role” of a biomarker and “when in the sequence of tumorigenesis it is expressed” assists in defining its utility for identifying premalignant disease, for making an early diagnosis and for developing a panel of biomarkers to predict tumour recurrence and progression. A paradigm for biomarker evaluation is evolving and requires the identification of single and multiple biomarker profiles.
Bladder cancer appears to develop along two separate pathways: a low-grade pathway seemingly associated with alterations on chromosome 9 and a second pathway associated with P-53 suppressor gene genetically altered on chromosome 17. Clearly, multiple genetic factors are related to cancer development, and defining the genetic factors in each individual is a difficult task, particularly when the genetic pathway must be linked to a complexity of perhaps multiple exposures. In epidemiological studies, exposures over prolonged intervals have been difficult to reconstruct. Batteries of phenotypic and genotypic markers are being identified to define individuals at risk in occupational cohorts. One profile of phenotypic biomarkers and their relationship to bladder cancer is shown in Figure 3, which illustrates that G-actin, a precursor protein to the cytoskeletal protein F-actin, is an early differentiation marker and may be followed by sequential alterations of other intermediate end-point markers such as M344, DD23 and DNA ploidy. The strongest biomarker panels for detecting premalignant disease and overt cancer, and for prognostication, remain to be determined. As machine-sensible biochemical criteria are defined it may be possible to detect disease risk at prescribed points in the disease continuum.
Figure 3. Four biomarkers, G-actin, P-300, DD23 and DNA, in relation to tumour progression and response to surgical treatment and chemoprevention.
Diagnosis and management of work-relatedrenal-urinary disease
Pre-existing renal disease
Changes in health care delivery systems worldwide bring into focus issues of insurability and protection of workers from additional exposure. Significant pre-existing renal disease is manifest by increased serum creatinine, glucosuria (sugar in the urine), proteinuria, haematuria and dilute urine. Immediately ruling out systemic underlying causes such as diabetes and hypertension is required, and depending on the age of the patient other congenital aetiologies such as multiple cysts in the kidney should be investigated. Thus, the urinalysis, both dipstick and microscopic evaluations, for detection of biochemical and cellular alterations, is useful to the occupational physician. Tests of serum creatinine and creatinine clearance are indicated if significant haematuria, pyuria or proteinuria suggests underlying pathology.
Multiple factors are important to assess risk for progression of chronic disease or acute kidney failure. The first is inherent or acquired limitation of the kidney to resist xenobiotic exposure. The kidney’s response to the nephrotoxicant, such as an increase in the amount of toxicant absorbed or alterations in kidney metabolism, may be influenced by a pre-existing condition. Of particular importance is a decrease in detoxifying function in the very young or the very old. In one study susceptibility to occupational exposure was correlated highly with family history of renal disease, signifying the importance of hereditary predisposition. Underlying conditions, such as diabetes and hypertension, increase susceptibility. Rare conditions, such as lupus erythematosis and vasculitis, may be additional susceptibility factors. In the majority of cases, increased susceptibility is multifactorial and frequently involves a battery of insults which occur either alone or simultaneously. Thus, the occupational physician should be cognizant of the patient’s family history of renal disease and pre-existing conditions affecting renal function, as well as any vascular or cardiac disease, particularly in older workers.
Acute renal failure
Acute renal failure may arise from pre-renal, renal, or post-renal causes. The condition is usually caused by an acute insult resulting in rapid, progressive loss of kidney function. When the nephrotoxicant or precipitating causal factor is removed there is a progressive return of renal function with a gradual decline of serum creatinine and improved renal concentrating ability. A listing of occupational causes of acute renal failure is shown in Table 5. Acute renal failure from high-dose xenobiotic exposure has been useful to signal potential aetiological causes that may also contribute to more chronic forms of progressive renal disease. Acute renal failure from obstruction of the outflow tract caused by benign disease or malignancy is relatively rare, but surgical causes may contribute more frequently. Ultrasound of the upper tract delineates the problem of obstruction, whatever the contributing factor. Renal failure associated with drug or occupational toxicants results in a mortality rate of approximately 37%; the remainder of affected individuals improve to various degrees.
Table 5. Principal causes of acute renal insufficiency of occupational origin
Renal ischaemia | Tubular necrosis | Haemoglobinuria, myoglobinuria |
Traumatic shock Anaphylactic shock Acute carbon monoxide poisoning Heat stroke |
Mercury Chromium Arsenic Oxalic acid Tartrates Ethylene glycol Carbon tetrachloride Tetrachlorethane |
Arsine Crush syndrome Struck by lightning |
Source: Crepet 1983.
Acute renal failure may be attributed to a variety of pre-renal causes which have as an underlying theme renal ischaemia resulting from a prolonged decreased renal perfusion. Cardiac failure and renal artery obstruction are two examples. Tubular necrosis may be caused by an ever-growing number of nephrotoxicants present in the workplace. Herbicides and pesticides have all been implicated in a number of studies. In a recent report, hemlock poisoning resulted in the deposition of the myosin and actin from the breakdown of muscle cells in the tubules and an acute decrease in renal function. Endosulfan, an insecticide, and triphenyltin acetate (TPTA), an organotin, both were initially classified as neurotoxins but have recently been reported to be associated with tubular necrosis. Anecdotal reports of additional cases bring into perspective the need for finding biomarkers to identify more subtle subclinical toxicants that may not yet have resulted in high-dose toxic exposures.
Signs and symptoms of acute renal failure are: no urine output (anuria); oliguria (decreased urine output); decreased renal concentrating capacity; and/or a rising serum potassium that may stop the heart in a relaxed state (diastolic arrest). Treatment involves clinical support and, whenever possible, removal from exposure to the toxicant. Rising serum potassium or excessive fluid retention are the two primary indicators for either haemodialysis or peritoneal dialysis, with the choice dependent on the patient’s cardiovascular stability and vascular access for haemodialysis. The nephrologist, a medical kidney specialist, is key in the management strategy for these patients who may also require the care of a urological surgical specialist.
Long-term management of patients following renal failure is largely dependent on the degree of recovery and rehabilitation and the patient’s overall health status. A return to limited work and avoiding conditions that will stress the underlying condition are desirable. Patients with persistent haematuria or pyuria require careful monitoring, possibly with biomarkers, for 2 years following recovery.
Chronic renal disease
Chronic or end-stage renal disease is most frequently the result of a chronic, ongoing subclinical process that involves a multiplicity of factors most of which are poorly understood. Glomerulonephritis, cardiovascular causes and hypertension are major contributing factors. Other factors include diabetes and nephrotoxicants. Patients present with progressive elevations in serum blood urea nitrogen, creatinine, serum potassium and oliguria (decreased urine output). Improved biomarkers or biomarker panels are needed to identify more precisely subclinical nephrotoxicity. For the occupational practitioner, the methods of assessment need to be non-invasive, highly specific and reproducible. No single biomarker has as yet met these criteria to become practical on a large clinical scale.
Chronic renal disease may result from a variety of nephrotoxicants, the pathogenesis of which is better understood for some than others. A list of nephrotoxicants and sites of toxicity is shown in Table 6. As mentioned, toxins may target the glomerulus, segments of the tubules or the interstitial cells. Symptoms of xenobiotic exposure may include haematuria, pyuria, glucosuria, amino acids in the urine, frequent urination and decreased urine output. The precise mechanisms of renal damage for many nephrotoxicants have not been defined but the identification of specific biomarkers of nephrotoxicity should assist in addressing this problem. Although some protection of the kidney is afforded by the prevention of vasoconstriction, tubular injury persists in most cases. As an example, lead toxicity is primarily vascular in origin, while chromium at low doses affects the proximal tubule cells. These compounds appear to affect the metabolic machinery of the cell. Multiple forms of mercury have been implicated in acute elemental nephrotoxicity. Cadmium, in contrast to mercury and like many other occupational nephrotoxicants, first targets the proximal tubule cells.
Table 6. Segments of the nephron affected by selected toxicants
Proximal tubule Antibiotics -Cephalosporins Aminoglycosides Antineoplastics -Nitrosoureas -Cisplatin and analogs Radiographic contrast agents Halogenated hydrocarbons -Chlorotrifluoroethylene -Hexafluropropene -Hexachlorobutadiene -Trichloroethylene -Chloroform -Carbon tetrachloride Maleic acid Citrinin Metals -Mercury -Uranyl nitrate -Cadmium -Chromium |
Glomerulus Immune complexes Aminoglycoside antibiotics Puromycin aminonucleoside Adriamycin Penicillamine Distal tubule/collecting duct -Lithium -Tetracyclines -Amphotericin -Fluoride -Methoxyflurane
Papilla -Aspirin -Phenacetin -Acetaminophen -Non-steroidal anti-inflammatory agents -2-Bromoethylamine |
Source: Tarloff and Goldstein 1994.
Adapted from 3rd edition, Encyclopaedia of Occupational Health and Safety. Revision includes information from A. Baiinova, J.F. Copplestone, L.A. Dobrobolskij,
F. Kaloyanova-Simeonova, Y.I. Kundiev and A.M. Shenker.
The word pesticide generally denotes a chemical substance (which may be mixed with other substances) that is used for the destruction of an organism deemed to be detrimental to humans. The word clearly has a very wide meaning and includes a number of other terms, such as insecticides, fungicides, herbicides, rodenticides, bactericides, miticides, nematocides and molluscicides, which individually indicate the organisms or pests that the chemical or class of chemicals is designed to kill. As different types of chemical agents are used for these general classes, it is usually advisable to indicate the particular category of pesticide.
General Principles
Acute toxicity is measured by the LD50 value; this is a statistical estimate of the number of mg of the chemical per kg of body weight required to kill 50% of a large population of test animals. The dose may be administered by a number of routes, usually orally or dermally, and the rat is the standard test animal. Oral or dermal LD50 values are used according to which route has the lower value for a specific chemical. Other effects, either as a result of short-term exposure (such as neurotoxicity or mutagenicity) or of long-term exposure (such as carcinogenicity), have to be taken into account, but pesticides with such known properties are not registered for use. The WHO Recommended Classification of Pesticides by Hazard and Guidelines to Classification 1996-1997 issued by the World Health Organization (WHO) classifies technical products according to the acute risk to human health as follows:
The guidelines based on the WHO Classification list pesticides according to toxicity and physical state; these are presented in a separate article in this chapter.
Poisons enter the body through the mouth (ingestion), the lungs (inhalation), the intact skin (percutaneous absorption) or wounds in the skin (inoculation). The inhalation hazard is determined by the physical form and solubility of the chemical. The possibility and degree of percutaneous absorption varies with the chemical. Some chemicals also exert a direct action on the skin, causing dermatitis. Pesticides are applied in many different forms—as solids, by spraying in dilute or concentrated form, as dusts (fine or granulated), and as fogs and gases. The method of use has a bearing on the likelihood of absorption.
The chemical may be mixed with solids (often with food used as bait), water, kerosene, oils or organic solvents. Some of these diluents have some degree of toxicity of their own and may influence the rate of absorption of the pesticide chemical. Many formulations contain other chemicals which are not themselves pesticides but which enhance the effectiveness of the pesticide. Added surface-active agents are a case in point. When two or more pesticides are mixed in the same formulation, the action of one or both may be enhanced by the presence of the other. In many cases, the combined effects of mixtures have not been fully worked out, and it is a good rule that mixtures should always be treated as more toxic than any of the constituents on their own.
By their very nature and purpose, pesticides have adverse biological effects on at least some species, human beings included. The following discussion provides a broad overview of the mechanisms by which pesticides can act, and some of their toxic effects. Carcinogenicity, biological monitoring and safeguards in the use of pesticides are discussed in more detail elsewhere in this Encyclopaedia.
Organochlorine Pesticides
The organochlorine pesticides (OCPs) have caused intoxication following skin contact, ingestion or inhalation. Examples are endrin, aldrin and dieldrin. The rate of absorption and toxicity differ depending on the chemical structure and the solvents, surfactants and emulsifiers used in the formulation.
The elimination of OCPs from the body takes place slowly through the kidneys. Metabolism in the cells involves various mechanisms—oxidation, hydrolysis and others. OCPs have a strong tendency to penetrate cell membranes and to be stored in the body fat. Because of their attraction to fatty tissues (lipotropic properties) OCPs tend to be stored in the central nervous system (CNS), liver, kidneys and the myocardium. In these organs they cause damage to the function of important enzyme systems and disrupt the biochemical activity of the cells.
OCPs are highly lipophilic and tend to accumulate in fatty tissue as long as exposure persists. When exposure ceases, they are released slowly into the bloodstream, often over a period of many years, from whence they can be transported to other organs where genotoxic effects, including cancer, may be initiated. The great majority of US residents, for example, have detectable levels of organochlorine pesticides, including breakdown products of DDT, in their adipose (fatty) tissue, and the concentrations increase with age, reflecting lifetime accumulations.
A number of OCPs that have been used throughout the world as insecticides and herbicides are also proven or suspected carcinogens to humans. These are discussed in more detail in the Toxicology and Cancer chapters of this Encyclopaedia.
Acute intoxications
Aldrin, endrin, dieldrin and toxaphene are most frequently implicated in acute poisoning. Delay in the onset of symptoms in severely acute intoxications is about 30 minutes. With lower toxicity OCPs it is several hours but not more than twelve.
Intoxication is demonstrated by gastrointestinal symptoms: nausea, vomiting, diarrhoea and stomach pains. The basic syndrome is cerebral: headache, dizziness, ataxia and paraesthesia. Gradually tremors set in, starting from the eyelids and the face muscles, descending towards the whole body and the limbs; in severe cases this leads to fits of tonic-clonic convulsions, which gradually extend to the different muscle groups. Convulsions may be connected with elevated body temperature and unconsciousness and may result in death. In addition to the cerebral signs, acute intoxications may lead to bulbar paralysis of the respiratory and/or vasomotor centres, which causes acute respiratory deficiency or apnoea, and to severe collapse.
Many patients develop signs of toxic hepatitis and toxic nephropathy. After these symptoms have disappeared some patients develop signs of prolonged toxic polyneuritis, anaemia and haemorrhagic diathesis connected with the impaired thrombocytopoiesis. Typical of toxaphene is an allergic bronchopneumonia.
Acute intoxications with OCPs last up to 72 hours. When organ function has been seriously impaired, the illness may continue up to several weeks. Complications in cases of liver and kidney damage can be long-lasting.
Chronic poisoning
During the application of OCPs in agriculture as well as in their production, poisoning is most commonly chronic—that is, low doses of exposure over time. Acute intoxication (or high-level exposures at a particular instant) are less common and are usually the result of misuse or accidents, both in the home and in industry. Chronic intoxication is characterized by damage to the nervous, digestive and cardiovascular systems and the blood-formation process. All OCPs are CNS stimulants and are capable of producing convulsions, which frequently appear to be epileptic in character. Abnormal electroencephalographic (EEG) data have been recorded, such as irregular alpha rhythms and other abnormalities. In some cases bitemporal sharp-peaked waves with shifting localization, low voltage and diffuse theta activity have been observed. In other cases paroxysmal emissions have been registered, composed of slow sharp-peaked waves, sharp-peaked complexes and rhythmic peaks with low voltage.
Polyneuritis, encephalopolyneuritis and other nervous system effects have been described following occupational exposure to OCPs. Tremor of the limbs and alterations in the electromyograms (EMGs) have also been observed in workers. In workers handling OCPs such as BHC, polychloropinene, hexachlorobutadiene and dichloroethane, non-specific signs (e.g., diencephalic signs) have been observed and very often develop together with other signs of chronic intoxication. The most common signs of intoxication are headache, dizziness, numbness and tingling in the limbs, rapid changes in blood pressure and other signs of circulatory disturbances. Less frequently, colic pains below the right ribs and in the region of the umbilicus, and dyskinesia of the bile ducts, are observed. Behavioural changes, such as disturbances of sensory and equilibrium functions, are found. These symptoms are often reversible after cessation of the exposure.
OCPs cause liver and kidney damage. Microsomal enzyme induction has been observed, and increased ALF and aldolase activity have also been reported. Protein synthesis, lipoid synthesis, detoxification, excretion and liver functions are all affected. Reduction of creatinine clearance and phosphorus reabsorption are reported in workers exposed to pentachlorophenol, for example. Pentachlorophenol, along with the family of chlorophenols, are also considered possible human carcinogens (group 2B as classified by the International Agency for Research on Cancer (IARC)). Toxaphene is also considered to be a group 2B carcinogen.
Cardiovascular disturbances have been observed in exposed persons, most frequently demonstrated as dyspnoea, high heart rate, heaviness and pain in the heart region, increased heart volume and hollow heart tones.
Blood and capillary disturbances have also been reported following contact with OCPs. Thrombopenia, anaemia, pancytopenia, agranulocytosis, haemolysis and capillary disorders have all been reported. Medullar aplasia can be complete. The capillary damage (purpura) can develop following long- or short-term but intensive exposures. Eosinopenia, neutropenia with lymphocytosis, and hypochromic anaemia have been observed in workers subjected to prolonged exposures.
Skin irritation is reported to follow from skin contact with some OCPs, particularly chlorinated terpenes. Often chronic intoxications are clinically demonstrated by signs of allergic damage.
Organophosphate Pesticides
The organophosphorus pesticides are chemically related esters of phosphoric acid or certain of its derivatives. The organic phosphates are also identified by a common pharmacological property—the ability to inhibit the action of the cholinesterase enzymes.
Parathion is among the most dangerous of the organophosphates and is discussed in some detail here. In addition to parathion’s pharmacological effects, no insect is immune to its lethal action. Its physical and chemical properties have rendered it useful as an insecticide and acaricide for agricultural purposes. The description of parathion’s toxicity applies to other organophosphates, although their effects may be less rapid and extensive.
The toxic action of all organic phosphates is on the CNS through inhibition of the cholinesterase enzymes. Inhibiting these cholinesterases produces excessive and continuous stimulation of those muscle and gland structures which are activated by acetylcholine, to a point where life can no longer be sustained. Parathion is an indirect inhibitor because it must be converted in the environment or in vivo before it can effectively inhibit cholinesterase.
Organophosphates can generally enter the body by any route. Serious and even fatal poisoning may occur by ingesting a small amount of parathion while eating or smoking, for example. Organophosphates may be inhaled when dusts or volatile compounds are even briefly handled. Parathion is easily absorbed through the skin or the eye. The ability to penetrate the skin in fatal quantities without the warning of irritation makes parathion especially difficult to handle.
Signs and symptoms of organophosphate poisoning can be explained on the basis of cholinesterase inhibition. Early or mild poisoning may be hard to distinguish because of a number of other conditions; heat exhaustion, food poisoning, encephalitis, asthma and respiratory infections share some of the manifestations and confuse the diagnosis. Symptoms can be delayed for several hours after the last exposure but rarely longer than 12 hours. Symptoms most often appear in this order: headaches, fatigue, giddiness, nausea, sweating, blurred vision, tightness in the chest, abdominal cramps, vomiting and diarrhoea. In more advanced poisoning, difficult breathing, tremors, convulsions, collapse, coma, pulmonary oedema and respiratory failure follow. The more advanced the poisoning, the more obvious are the typical signs of cholinesterase inhibition, which are: pinpoint pupils; rapid, asthmatic type breathing; marked weakness; excessive sweating; excessive salivation; and pulmonary oedema.
In very severe parathion poisoning, in which the victim has been unconscious for some time, brain damage from anoxia may occur. Fatigue, ocular symptoms, electroencephalogram abnormalities, gastrointestinal complaints, excessive dreams and exposure intolerance to parathion have been reported to persist for days to months following acute poisoning. There is no evidence that permanent impairment occurs.
Chronic exposure to parathion may be cumulative in the sense that repeated exposures closely following each other can reduce cholinesterase faster than it can be regenerated, to the point where a very small exposure can precipitate acute poisoning. If the person is removed from exposure, clinical recovery is usually rapid and complete within a few days. The red blood cells and plasma should be tested for cholinesterase inhibition when phosphate ester poisoning is suspected. Red cell cholinesterase activity is most often reduced and close to zero in severe poisoning. Plasma cholinesterase is also severely reduced and is a more sensitive and more rapid indicator of exposure. There is no advantage in chemical determinations of parathion in the blood because metabolism of the pesticide is too rapid. However, p-nitrophenol, an end-product of the metabolism of parathion, can be determined in the urine. Chemical examination to identify the pesticide can be made on contaminated clothing or other material where contact is suspected.
Carbamates and Thiocarbamates
The biological activity of carbamates was discovered in 1923 when the structure of the alkaloid eserine (or physostigmine) contained in the seeds of Calabar beans was first described. In 1929 physostigmine analogues were synthesized, and soon such derivatives of dithiocarbamic acid as thiram and ziram were available. The study of carbamic compounds began in the same year, and now more than 1,000 carbamic acid derivatives are known. More than 50 of them are used as pesticides, herbicides, fungicides and nematocides. In 1947 the first carbamic acid derivatives having insecticide properties were synthesized. Some thiocarbamates have proved effective as vulcanization accelerators, and derivatives of dithiocarbamic acid have been obtained for the treatment of malignant tumours, hypoxia, neuropathies, radiation injuries and other diseases. Aryl esters of alkylcarbamic acid and alkyl esters of arylcarbamic acid are also used as pesticides.
Some carbamates can produce sensitization in exposed individuals, and a variety of foetotoxic, embryotoxic and mutagenic effects have also been observed for members of this family.
Chronic effects
The specific effects produced by acute poisoning have been described for each substance listed. A review of the specific effects gained from an analysis of published data makes it possible to distinguish similar features in the chronic action of the different carbamates. Some authors believe that the main toxic effect of carbamic acid esters is the involvement of the endocrine system. One of the peculiarities of carbamate poisoning is the possible allergic reaction of exposed subjects. The toxic effects of carbamates may not be immediate, which can present a potential hazard because of lack of warning. Results from animal experiments are indicative of embryotoxic, teratogenic, mutagenic and carcinogenic effects of some carbamates.
Baygon (isopropoxyphenyl-N-methylcarbamate) is produced by reaction of alkyl isocyanate with phenols, and is used as an insecticide. Baygon is a systemic poison. It causes inhibition of the serum cholinesterase activity up to 60% after oral administration of 0.75 to 1 mg/kg. This highly toxic substance exerts a weak effect on the skin.
Carbaryl is a systemic poison which produces moderately severe acute effects when ingested, inhaled or absorbed through the skin. It may cause local skin irritation. Being a cholinesterase inhibitor, it is much more active in insects than in mammals. Medical examinations of workers exposed to concentrations of 0.2 to 0.3 mg/m3 seldom reveal a fall in cholinesterase activity.
Betanal (3-(methoxycarbonyl)aminophenyl-N-(3-methylphenyl) carbamate; N-methylcarbanilate) belongs to the arylcarbamic acid alkyl esters and is used as a herbicide. Betanal is slightly toxic for the gastrointestinal and respiratory tracts. Its dermal toxicity and local irritation are insignificant.
Isoplan is a highly toxic member of the group, its action, like that of Sevin and others, being characterized by the inhibition of acetylcholinesterase activity. Isoplan is used as an insecticide. Pyrimor (5,6-dimethyl-2-dimethylamino-4-pyrimidinyl methylcarbamate) is a derivative of arylcarbamic acid alkyl esters. It is highly toxic for the gastrointestinal tract. Its general absorption and local irritative effect are not very pronounced.
Thiocarbamic Acid Esters
Ronite (sym-ethylcyclohexylethyl thiocarbamate; Eurex); Eptam (sym-ethyl-N,N-dipropyl thiocarbamate); and Tillam (sym-propyl-N-ethyl-N-butylthiocarbamate) are esters which are synthesized by reaction of alkylthiocarbamates with amines and of alkaline mercaptides with carbamoyl chlorides. They are effective herbicides of selective action.
The compounds of this group are slightly to moderately toxic, and the toxicity is reduced when they are absorbed through the skin. They can affect the oxidative processes as well as the nervous and endocrine systems.
Dithiocarbamates and bisdithiocarbamates include the following products, which have much in common as regards their use and their biological effects. Ziram is used as a vulcanization accelerator for synthetic rubbers and, in agriculture, as a fungicide and seed fumigant. This compound is very irritant to the conjunctiva and upper airway mucous membranes. It can cause extreme pain in the eyes, skin irritation and liver function disorders. It has embryotoxic and teratogenic effects. TTD is used as a seed fumigant, irritates the skin, causes dermatitis and affects the conjunctiva. It increases sensitivity to alcohol. Nabam is a plant fungicide and serves as an intermediate in the production of other pesticides. It is irritating to the skin and mucous membranes, and it is a narcotic in high concentrations. In the presence of alcohol it can cause violent vomiting. Ferbam is a fungicide of relatively low toxicity, but may cause renal function disorders. It irritates the conjunctiva, the mucous membranes of the nose and upper airways, and the skin.
Zineb is an insecticide and fungicide that can cause irritation of the eyes, nose and larynx, and is harmful if inhaled or swallowed. Maneb is a fungicide that can cause irritation of the eyes, nose and larynx, and is harmful if inhaled or swallowed. Vapam (sodium methyldithiocarbamate; carbation) is white crystalline powder of unpleasant smell similar to that of carbon disulphide. It is an effective soil fumigant which destroys weed seeds, fungi and insects. It irritates the skin and mucous membranes.
Rodenticides
Rodenticides are toxic chemicals used for the control of rats, mice and other pest species of rodents. An effective rodenticide must conform to stringent criteria, a fact that is borne out by the small number of compounds that are currently in satisfactory use.
Poisoned baits are the most generally effective and widely used means of formulating rodenticides, but some are used as “contact” poisons (i.e., dusts, foams and gels), where the toxicant adheres to the fur of the animal and is ingested during subsequent grooming, while a few are applied as fumigants to burrows or infested premises. Rodenticides may conveniently be divided into two categories, depending on their mode of action: acute (single dose) poisons and chronic (multiple dose) poisons.
Acute poisons, such as zinc phosphide, norbormide, fluoracetamide, alpha-chloralose, are highly toxic compounds, with LD50s that are usually less than 100 mg/kg, and can cause death after a single dose consumed during a period not longer than a few hours.
Most acute rodenticides have the disadvantages of producing symptoms of poisoning rather quickly, of being generally rather non-specific, and lacking satisfactory antidotes. They are used at relatively high concentrations (0.1 to 10%) in bait.
Chronic poisons, which may act, for example, as anticoagulants (e.g., calciferol), are compounds that, having a cumulative mode of action, may need to be eaten by the prey over a succession of days to cause death. Anticoagulants have the advantage of producing symptoms of poisoning very late, usually well after the target species has eaten a lethal dose. An effective antidote to anticoagulants is available for those accidentally exposed. Chronic poisons are used at relatively low concentrations (0.002 to 0.1%).
Application
Rodenticides intended for use in baits are available in one or more of the following forms: technical grade material, concentrate (“master-mix”) or ready-to-use bait. Acute poisons are usually acquired as the technical material and mixed with the bait-base shortly before use. Chronic poisons, because they are used at low concentrations, are normally sold as concentrates, where the active ingredient is incorporated into a finely powdered flour (or talc) base.
When the final bait is prepared, the concentrate is added to the bait-base at the relevant rate. If the bait-base is of a coarse consistency, it may be necessary to add a vegetable or mineral oil at a prescribed rate to act as a “sticker”, thus ensuring that the poison adheres to the bait-base. It is commonly compulsory for a warning dye to be added to concentrates or ready-to-use baits.
In control treatments against rats and mice, poisoned baits are laid at frequent intervals throughout the infested area. When acute rodenticides are used, better results are obtained when unpoisoned bait (“prebait”) is laid for a few days before the poison is given. In “acute” treatments, poisoned bait is presented for a few days only. When anticoagulants are used, prebaiting is unnecessary, but the poison should remain in position for 3 to 6 weeks to achieve complete control.
Contact formulations of rodenticides are especially useful in situations where baiting is difficult for any reason, or where the rodents are not being drawn satisfactorily off their normal diet. The poison is usually incorporated in a finely divided powder (e.g., talc), which is laid on runways or around bait points, or is blown into burrows, wall cavities and so on. The compound may also be formulated in gels or foams, which are inserted into burrows.
The use of contact rodenticides relies on the target animal ingesting the poison while grooming itself. Because the amount of dust (or foam, etc.) adhering to the fur may be small, the concentration of the active ingredient in the formulation is usually relatively high, making it safe to use only where the contamination of food and so on cannot occur. Other specialized formulations of rodenticides include water baits and wax-impregnated blocks. The former, which are aqueous solutions of soluble compounds, are especially useful in dry environments. The latter are made by impregnating the toxicant and bait-base in molten paraffin wax (of low melting point) and casting the mixture into blocks. Wax-impregnated baits are designed to withstand wet climates and insect attack.
Hazards of rodenticides
Although toxicity levels of rodenticides may vary between target and non-target species, all poisons must be presumed to be potentially lethal to humans. Acute poisons are potentially more dangerous than chronic ones because they are rapid in action, non-specific and generally lack effective antidotes. Anticoagulants, on the other hand, are slow and cumulative, allowing adequate time for the administration of a reliable antidote, such as vitamin K.
As stated above, the concentrations of active ingredients in contact formulations of a given poison are higher than those in bait preparations, thus making operator hazard considerably greater. Fumigants present a special danger when used to treat infested premises, holds of ships and so on, and should be used only by trained technicians. The gassing of rodent burrows, although less hazardous, must also be carried out with extreme caution.
Herbicides
Grassy and broad-leaved weeds compete with crop plants for light, space, water and nutrients. They are hosts to bacteria, fungi and viruses, and hamper mechanical harvesting operations. Losses in crop yields as a result of weed infestation can be very heavy, commonly reaching 20 to 40%. Weed-control measures such as hand weeding and hoeing are ineffective in intensive farming. Chemical weedkillers or herbicides have successfully replaced mechanical methods of weed control.
In addition to their use in agriculture in cereals, meadows, open fields, pastures, fruit growing, greenhouses and forestry, herbicides are applied on industrial sites, railway tracks and power lines to remove vegetation. They are used for destroying weeds in canals, drainage channels and natural or artificial pools.
Herbicides are sprayed or dusted on weeds or on the soil they infest. They remain on the leaves (contact herbicides) or penetrate into the plant and so disturb its physiology (systemic herbicides). They are classified as non-selective (total—used to kill all vegetation) and selective (used to suppress the growth of or kill weeds without damaging the crop). Both non-selective and selective can be contact or systemic.
Selectivity is true when the herbicide applied in the correct dose and, at the right time, is active against certain species of weed only. An example of true selective herbicides are the chlorophenoxy compounds, which affect broad-leaved but not grassy plants. Selectivity can also be achieved by placement (i.e., by using the herbicide in such a way that it comes into contact with the weeds only). For example, paraquat is applied to orchard crops, where it is easy to avoid the foliage. Three types of selectivity are distinguished:
1. physiological selectivity, which relies upon the plant’s ability to degrade the herbicide into non-phytotoxic components
2. physical selectivity, which exploits the particular habit of the cultivated plant (e.g., the upright in cereals) and/or a specially fashioned surface (e.g., wax-coating, resistant cuticule) protecting the plant against herbicide penetration
3. positional selectivity, in which the herbicide remains fixed in the upper soil layers adsorbed on colloidal soil particles and does not reach the root zone of the cultivated plant, or at least not in harmful quantities. Positional selectivity depends on the soil, precipitation and temperature as well as the water solubility and soil adsorption of the herbicide.
Some commonly used herbicides
Following are brief descriptions of acute and chronic effects associated with some commonly used herbicides.
Atrazine gives rise to decreased body weight, anaemia, disturbed protein and glucose metabolism in rats. It causes occupational contact dermatitis due to skin sensitization. It is considered a possible human carcinogen (IARC group 2B).
Barban, in repeated contact with 5% water emulsion, causes severe skin irritation in rabbits. It provokes skin sensitization in both experimental animals and agricultural workers, and causes anaemia, methaemoglobinaemia and changes in lipid and protein metabolism. Ataxia, tremor, cramps, bradycardia and ECG deviations are found in experimental animals.
Chlorpropharm can produce slight dermal irritation and penetration. In rats, exposure to atrazine causes anaemia, methaemoglobinaemia and reticulocytosis. Chronic application causes skin carcinoma in rats.
Cycloate causes polyneuropathia and liver damage in experimental animals. No clinical symptoms have been described after occupational exposure of workers for three consecutive days.
2,4-D poses moderate dermal toxicity and skin irritancy risks to exposed persons. It is highly irritating to the eyes. Acute exposures in workers provoke headache, dizziness, nausea, vomiting, raised temperature, low blood pressure, leucocytosis, and heart and liver injury. Chronic occupational exposure without protection may cause nausea, liver functional changes, contact toxic dermatitis, irritation of airways and eyes, as well as neurological changes. Some of the derivatives of 2,4-D are embryotoxic and teratogenic for experimental animals in high doses only.
2,4-D and the related phenoxy herbicide 2,4,5-T are rated as group 2B carcinogens (possible human carcinogens) by the IARC. Lymphatic cancers, particularly non-Hodgkin lymphoma (NHL), have been associated in Swedish agricultural workers with exposure to a commercial mixture of 2,4-D and 2,4,5-T (similar to the herbicide Agent Orange used by the US military in Viet Nam during the years 1965 to 1971). Possible carcinogenicity is often ascribed to contamination of 2,4,5-T with 2,3,7,8-tetrachloro-dibenzo-p-dioxin. However, a US National Cancer Institute research group reported a risk of 2.6 for adult NHL among Kansas residents exposed to 2,4-D alone, which is not thought to be dioxin-contaminated.
Dalapon-Na can cause depression, an unbalanced gait, decreased body weight, kidney and liver changes, thyroid and pituitary dysfunctions, and contact dermatitis in workers who are exposed. Diallate has dermal toxicity and causes irritation to the skin, eyes and mucous membranes. Diquat is an irritant to the skin, eyes and upper respiratory tract. It can cause a delay in the healing of cuts and wounds, gastrointestinal and respiratory disturbances, bilateral cataract and functional liver and kidney changes.
Dinoseb presents dangers because of its toxicity through dermal contact. It can cause moderate skin and pronounced eye irritation. The fatal dose for humans is about 1 to 3 g. After an acute exposure, Dinoseb causes central nervous system disturbances, vomiting, reddening (erythema) of the skin, sweating and high temperature. Chronic exposure without protection results in decreased weight, contact (toxic or allergic) dermatitis and gastrointestinal, liver and kidney disturbances. Dinoseb is not used in many countries because of its serious adverse effects.
Fluometuron is a moderate skin sensitizer in guinea-pigs and humans. It has been observed to cause decreased body weight, anaemia, and liver, spleen and thyroid gland disturbances. The biological action of diuron is similar.
Linuron causes mild irritation to the skin and eyes, and has low cumulative toxicity (threshold value after single inhalation 29 mg/m3). It causes CNS, liver, lung and kidney changes in experimental animals, as well as thyroid dysfunction.
MCPA is highly irritant to skin and mucous membranes, has low cumulative toxicity and is embryotoxic and teratogenic in high doses in rabbits and rats. Acute poisoning in humans (an estimated dose of 300 mg/kg) results in vomiting, diarrhoea, cyanosis, mucus burns, clonic spasms, and myocardium and liver injury. It provokes severe contact toxic dermatitis in workers. Chronic exposure without protection results in dizziness, nausea, vomiting, stomach aches, hypotonia, enlarged liver, myocardium dysfunction and contact dermatitis.
Molinate can reach a toxic concentration after single inhalation of 200 mg/m3 in rats. It causes liver, kidney and thyroid disturbances, and is gonadotoxic and teratogenic in rats. It is a moderate skin sensitizer in humans.
Monuron in high doses can result in liver, myocardium and kidney disturbances. It causes skin irritation and sensitization. Similar effects are shown by monolinuron, chloroxuron, chlortoluron and dodine.
Nitrofen is a strong skin and eye irritant. Chronic occupational exposure without protection results in CNS disturbances, anaemia, raised temperature, decreased body weight, fatigue and contact dermatitis. It is considered a possible human carcinogen (group 2B) by the IARC.
Paraquat has dermal toxicity and irritant effects on skin or mucous membranes. It causes nail damage and nose bleeding in occupational conditions without protection. Accidental oral poisoning with paraquat has resulted when it was left within reach of children or transferred from the original container into a bottle used for a beverage. Early manifestations of such intoxication are corrosive gastrointestinal effects, renal tubular damage and liver dysfunction. Death is due to circulatory collapse and progressive pulmonary damage (pulmonary oedema and haemorrhage, intra-alveolar and interstitial fibrosis with alveolitis and hyaline membranes), clinically revealed by dyspnoea, hypoxaemia, basal rales and roentgenographic evidence of infiltration and athelectasis. The renal failure is followed by lung damage, and accompanied in some cases by liver or myocardium disturbances. Mortality is higher with poisoning from liquid concentrate formulations (87.8%), and lower from granular forms (18.5%). The fatal dose is 6 g paraquat ion (equivalent to 30 ml Gramoxone or 4 packets of Weedol), and no survivors are reported at greater doses, irrespective of the time or vigour of treatment. Most survivors had ingested less than 1 g paraquat ion.
Potassium cyanate is associated with high inhalation and dermal toxicity in experimental animals and humans due to the metabolic conversion to cyanide, which is discussed elsewhere in this Encyclopaedia.
Prometryn exhibits moderate dermal toxicity and skin and eye irritation. It provokes decreased clotting and enzyme abnormalities in animals and has been found to be embryotoxic in rats. Exposed workers may complain of nausea and sore throat. Analogous effects are shown by propazine and desmetryne.
Propachlor’s toxicity is doubled at high environmental temperatures. Skin and mucous membrane irritation and mild skin allergy are associated with exposure. The toxic concentration after single inhalation is 18 mg/m3 in rats, and it is thought to exhibit moderate cumulative toxicity. Propachlor causes polyneuropathies; liver, myocardium and kidney disturbances; anaemia; and damage to testes in rats. During spraying from the air, the concentration in the spray cabin has been found to be about 0.2 to 0.6 mg/m3. Similar toxic properties are shown by propanil.
Propham exhibits moderate cumulative toxicity. It causes haemodynamic disturbances, and liver, lung and kidney changes are found in experimental animals.
Simazine causes slight irritation of the skin and mucous membranes. It is a moderate skin sensitizer in guinea-pigs. It also causes CNS, liver and kidney disturbances and has mutagenic effect in experimental animals. Workers may complain of weariness, dizziness, nausea and olfactory deviations after application without protective equipment.
2,4,5-T causes pronounced irritation and embryotoxic, teratogenic and carcinogenic effects in animals; there are also data on its gonadotoxic action in women. Because the extremely toxic chemical dioxin can be a contaminant of the trichlorophenoxy acids, use of 2,4,5-T is prohibited in many countries. Agricultural, forestry and industrial workers exposed to mixtures of 2,4-D and 2,4,5-T have been reported at increased risk for both soft-tissue sarcomas and non-Hodgkin lymphomas.
Trifluralin causes slight irritation of skin and mucous membranes. An increased incidence of liver carcinoma has been found in hybrid female mice, probably due to contamination with N-nitroso compounds. Trifluralin causes anaemia and liver, myocardium and kidney changes in experimental animals. Extensively exposed workers have developed contact dermatitis and photodermatitis.
Fungicides
Some fungi, such as rusts, mildews, moulds, smuts, storage rots and seedling blights, are able to infect and cause diseases in plants, animals and humans. Others can attack and destroy non-living materials such as wood and fibre products. Fungicides are used to prevent these diseases and are applied by spraying, dusting, seed dressing, seedling and soil sterilization, and fumigation of warehouses and greenhouses.
Fungi causing plant diseases can be arranged into four sub-groups, which differ by the microscopic characters of the mycelium, the spores and the organs on which the spores were developed:
1. phycomycetes—soil-borne organisms causing club rot of brassicae, wart diseases of potatoes and so on
2. ascomycetes—perithecia-forming powdery mildews and fungi causing apple scab, black currant leaf spot and rose black spot
3. basidiomycetes, including loose smut of wheat and barley, and several rusts species
4. fungi imperfecti, which includes the genera Aspergillus, Fusarium, Penicillium and so on, that are of great economic importance because they cause significant losses during plant growth, at harvest, and after harvest. (e.g., Fusarium species infect barley, oats and wheat; Penicillium species cause brown rot of pomaceous fruit).
Fungicides have been used for centuries. Copper and sulphur compounds were the first to be used, and Bordeaux mixture was applied in 1885 to vineyards. A great number of widely differing chemical compounds with fungicidal action are used in many countries.
Fungicides can be classified into two groups according to their mode of action: protective fungicides (applied at a time prior to the arrival of the fungal spores—e.g., sulphur and copper compounds) or eradicant fungicides (applied after the plant has become infected—e.g., mercury compounds and nitroderivatives of the phenols). The fungicides either act on the surface of the leaves and seeds or penetrate into the plant and exert their toxic action directly on the fungi (systemic fungicides). They can also alter the physiological and biochemical processes in the plant and thus produce artificial chemical immunization. Examples of this group are the antibiotics and the rodananilides.
Fungicides applied to seed act primarily against surface-borne spores. However, in some cases they are required to persist on the seed coat long enough to be effective against the dormant mycelium contained within the seed. When applied to the seed before sowing, the fungicide is called seed disinfectant or seed dressing, though the latter term may include treatment not intended to counter seed-borne fungi or soil pests. To protect wood, paper, leather and other materials, fungicides are used by impregnation or staining. Special drugs with fungicidal action are also used to control fungal diseases in humans and animals.
Specific field applications include:
Hazards of fungicides
The fungicides cover a great variety of chemical compounds differing widely in their toxicity. Highly toxic compounds are used as fumigants of foods and warehouses, for seed dressing and for soil disinfection, and cases of poisoning have been described with organomercurials, hexachlorobenzene and pentachlorobenzene, as well as with the slightly toxic dithiocarbamates. These and several other chemicals are discussed in more detail elsewhere in this article, chapter and Encyclopaedia. Some are briefly reviewed here.
Chinomethionate has a high cumulative toxicity and inhibits thiol groups and some enzymes containing them; it lowers phagocytic activity and has antispermatogenic effects. It is irritant to the skin and the respiratory system. It can damage the CNS, the liver and the gastrointestinal tract. Glutathione and cysteine provide protection against the acute effects of chinomethionate.
Chloranil is irritating to the skin and the upper respiratory tract; it can also cause depression of the CNS and dystrophic changes in the liver and kidney. The biological monitoring of exposed persons has shown an increased level of the urinary phenols, both free and bound.
Dazomet is used also as a nematocide and a slimicide. This compound and its decomposition products are sensitizers and mild irritants of the eye, nose, mouth and skin. Poisoning is characterized by a variety of symptoms, including anxiety, tachycardia and quick breathing, hypersalivation, clonic cramps, impaired movement coordination, sometimes hyperglycaemia and cholinesterase inhibition. The main pathomorphological findings are enlargement of the liver and degenerative changes of the kidney and other internal organs.
Dichlofluanid inhibits thiol groups. In experimental animals it caused histological changes in liver, proximal tubules of the kidney and adrenal cortex, with the reduction of the lymphatic tissue in the spleen. It is a moderate irritant of the skin and mucous membranes.
Diclone, in addition to sharing the irritant and blood depressant properties common to quinones, is an experimental animal carcinogen.
Dinobuton, like dinitro-o-cresol (DNOC), disturbs cell metabolism by inhibiting oxidative phosphorylation, with the loss of energy-rich compounds such as adenosintriphosphoric acid (ATP). It can cause severe liver dystrophy and necrosis of the convoluted tubules of the kidneys. The clinical manifestations of the intoxication are high temperature, methaemoglobinaemia and haemolysis, nervous disturbances and irritation of the skin and mucous membranes.
Dinocap can increase the blood level of alkaline phosphatase and is a moderate irritant of the skin and mucous membranes. It produces distrophic changes in the liver and kidney, and hypertrophy of the myocardium. In acute poisoning, disturbances in thermoregulation, clonic cramps and breathing difficulties have been observed.
Hexachlorobenzene (HCB) is stored in the body fat. It interferes with porphyrin metabolism, increasing the urinary excretion of coproporphyrins and uroporphyrins; it increases also the levels of transaminases and dehydrogenases in the blood. It can produce liver injury (hepatomegaly and cirrhosis), photosensitization of the skin, a porphyria similar to porphyria cutanea tarda, arthritis and hirsutism (monkey disease). It is a skin irritant. Chronic poisoning needs long-term treatment, mainly symptomatic, and it is not always reversible on cessation of exposure. It is classified as a possible human carcinogen (group 2B) by the IARC.
Milneb can cause gastrointestinal disturbances, weakness, decrease of the body temperature and leukopoenia.
Nirit has haemotoxic properties and causes anaemia and leucocytosis with toxic granulation of the leucocytes, in addition to degenerative changes in the liver, spleen and kidneys.
Quinones, in general, cause blood disturbances (methaemoglobinaemia, anaemia), affect the liver, disturb vitamin metabolism, particularly that of ascorbic acid, and are irritant to the respiratory ways and the eye. Chloranil and dichlone are the quinone derivatives most widely used as fungicides.
Thiabendazole has caused thymus involution, colloid depletion in the thyroid and increase in liver and kidney size. It is also used as an anthelmintic in cattle.
Safety and Health Measures
Labelling and storage
The requirements regarding the labelling of pesticides laid down in national and international legislation should be strictly applied to both imported and locally produced chemicals. The label should give the following essential information: both the approved name and the trade name of the chemical; the name of the manufacturer, packager or supplier; the directions for use; the precautions to be taken during use, including details of protective equipment to be worn; the symptoms of poisoning; and the first-aid treatment for suspected poisoning.
The greater the degree of toxicity or hazard of the chemical, the more precise should be the wording on the label. It is sound practice for the different classes to be clearly distinguished by background colours on the label and, in the case of compounds of high or extreme hazard, for the appropriate danger symbol to be incorporated. It often occurs that an adequately labelled quantity of pesticide in bulk is locally repacked into smaller containers. Each such small package should bear a similar label, and repacking in containers which have held, or are easily identifiable with, containers used for food should be absolutely forbidden. If small packages are to be transported, the same rules apply as for the carriage of larger packages. (See the chapter Using, storing and transporting chemicals.)
Pesticides of moderate or higher hazard should be so stored that only authorized persons can have access to them. It is particularly important that children should be excluded from any contact with pesticide concentrates or residues. Spillages often occur in storage and repacking rooms, and they must be cleaned up with care. Rooms used only for storage should be soundly constructed and fitted with secure locks. Floors should be kept clear and the pesticides clearly identified. If repacking is carried out in storage rooms, adequate ventilation and light should be available; floors should be impervious and sound; washing facilities should be available; and eating, drinking and smoking should be prohibited in the area.
A few compounds react with other chemicals or with air, and this has to be taken into account when planning storage facilities. Examples are cyanide salts (which react with acid to produce hydrogen cyanide gas) and dichlorvos (which vaporizes in contact with air). (Dichlorvos is classified as a group 2B possible human carcinogen by the IARC.).
Mixing and application
Mixing and application may comprise the most hazardous phase of the use of pesticides, since the worker is exposed to the concentrate. In any particular situation, only selected persons should be responsible for mixing; they should be thoroughly conversant with the hazards and provided with the proper facilities for dealing with accidental contamination. Even when the mixed formulation is of such a toxicity that it can be used with a minimum of personal protective equipment (PPE), more elaborate equipment may need to be provided for and used by the mixer.
For pesticides of moderate or higher hazard, some type of PPE is almost always necessary. The choice of particular items of equipment will depend on the hazard of the pesticide and the physical form in which it is being handled. Any consideration of PPE must also include not only provision but also adequate cleaning, maintenance and replacement.
Where climatic conditions preclude the use of some types of PPE, three other principles of protection can be applied—protection by distance, protection by time and protection by change of working method. Protection by distance involves modification of the equipment used for application, so that the person is as far away as possible from the pesticide itself, bearing in mind the likely routes of absorption of a specific compound.
Protection by time involves limitation of hours of work. The suitability of this method depends on whether the pesticide is readily excreted or whether it is cumulative. Accumulation of some compounds occurs in the body when the rate of excretion is slower than the rate of absorption. With some other compounds, a cumulative effect may occur when the person is exposed to repeated small doses which, taken individually, may not give rise to symptoms.
Protection by change of working method involves a reconsideration of the whole operation. Pesticides differ from other industrial processes in that they can be applied from the ground or the air. Changes of method on the ground depend largely on the choice of equipment and the physical nature of the pesticide to be applied.
Pesticides that are applied from the air can be in the form of liquids, dusts or granules. Liquids may be sprayed from very low altitudes, frequently as fine droplets of concentrated formulations, known as ultra-low volume (ULV) applications. Drift is a problem particularly with liquids and dusts. Aerial application is an economical way of treating large tracts of land but entails special hazards to pilots and to workers on the ground. Pilots can be affected by leakage from hoppers, by pesticides carried into the cockpit on clothes and boots, and by flying back through the swathe just released or through the drift from the swathe. Even minor degrees of absorption of some pesticides or their local effects (such as may be caused, for instance, by an organophosphorus compound in the eye) can affect a pilot to the extent that he or she cannot maintain the high degree of vigilance necessary for low flying. Pilots should not be allowed to engage in pesticide operations unless they have been specially trained in the items listed above, in addition to any special aviation and agricultural operational requirements.
On the ground, loaders and flaggers may be affected. The same principles apply to loaders as to others dealing with pesticides in bulk. Flaggers mark the swathe to be flown and can be severely contaminated if the pilot misjudges the moment of release. Balloons or flags can be placed in position before or ahead of the operation, and workers should never be used as flaggers within the flight pattern.
Other restrictions
The hazards associated with pesticides do not end with their application; with the more toxic compounds it has been shown that there is a danger to workers entering a sprayed crop too soon after application. It is therefore important that all workers and members of the general public should be informed concerning the areas where a toxic pesticide has been applied and the earliest date on which it is safe to enter and work in these areas. Where a food crop has been sprayed, it is also important that the crop not be harvested until a sufficient period has elapsed for degradation of the pesticide to take place, in order to avoid excessive residues on food.
Disposal of pesticides and containers. Spillage of pesticides at any stage of their storage or handling should be treated with great care. Liquid formulations may be reduced to solid phase by evaporation. Dry sweeping of solids is always hazardous; in the factory environment, these should be removed by vacuum cleaning or by dissolving them in water or other solvent. In the field they may be washed away with water into a suitable soak-hole. Contaminated topsoil should be removed and buried if any domestic animals or fowls are in the area. Soak-holes should be used for disposing of washing waters from cleaning application equipment, clothing or hands. These should be at least 30 cm deep and sited well away from wells or watercourses.
Empty pesticide containers should be collected with care, or disposed of safely. Plastic liners, and paper or card containers should be crushed and buried well below the topsoil or burned, preferably in an incinerator. Metal containers of some pesticides can be decontaminated according to the instructions of the pesticide manufacturers. Such drums should be clearly marked “Not to be used for food or for water for drinking or domestic use”. Other metal containers should be punctured, crushed or buried.
Hygiene and first aid
Where a pesticide is of moderate or higher hazard and can be readily absorbed through the skin, special precautions are necessary. In some situations where workers may become accidentally contaminated with large quantities of concentrate, such as in factory situations and mixing, it is necessary to provide a shower bath in addition to the usual washing facilities. Special arrangements for cleaning clothing and overalls may be necessary; in any case, these should not be left for the worker to wash at home.
Since pesticides are often applied outside the factory environment, depending on the chemical used, special care may have to be taken to provide washing facilities at the workplace, even though this may be in remote fields. Workers must never bathe themselves in canals and rivers, the water from which may be subsequently used for other purposes; the washing water provided should be disposed of with care as outlined above. Smoking, eating and drinking before washing should be absolutely prohibited when any pesticide of moderate or higher toxicity is being handled or used.
Where an antidote exists which can be readily used as a first-aid measure for a specific pesticide (e.g., atropine for organophosphorus poisoning), it should be readily available to workers, who should be instructed in the method of its use. When any pesticide is being used on a substantial scale, medical personnel in the area should be informed by the persons responsible for distribution. The nature of the chemical used should be well defined so that medical facilities can be equipped and will know the specific antidotes, where these are applicable and how to recognize cases of poisoning. Facilities should also be available in order to make proper differential diagnosis, even if these are of the simplest type, such as test papers for determining cholinesterase levels. Strict routine medical supervision of workers heavily exposed to concentrates, as in the manufacture and packing of pesticides, is essential and should include laboratory tests and routine surveillance and record keeping.
Training
While all workers using pesticide formulations of moderate or higher hazard should be thoroughly trained in their use, such training is particularly important if the pesticide is extremely toxic. Training programmes must cover: toxicity of compounds used and routes of absorption; handling of concentrates and formulations; methods of use; cleaning of equipment; precautions to be taken and PPE to be worn; maintenance of PPE; avoidance of contamination of other crops, foods and water supplies; early symptoms of poisoning; and first-aid measures to be taken. All training should be strictly relevant to the pesticide actually being used, and, in the case of extremely hazardous compounds, it is wise to license operators following an examination to show that they have, in fact, a good understanding of the hazards and the procedures to be followed.
Public health measures
When pesticides are used, every effort must be made to avoid contamination of water supplies, whether these are officially recognized supplies or not. This not only concerns the actual application (when there may be immediate contamination) but must also include consideration of remote contamination by run-off through rainfall on recently treated areas. While pesticides in natural watercourses may be diluted to such a degree that the contaminated water may not be hazardous in itself, the effect on fish, on water vegetables used as food and grown in the watercourses, and on wild life as a whole must not be overlooked. Such hazards may be economic rather than directly related to health, but are no less important.
Agricultural chemicals are usually defined as pesticides, fertilizers and health products. The US Environmental Protection Agency (EPA) defines pesticides as any materials manufactured or formulated to kill a pest. This means that herbicides, fungicides, insecticides and miticides are pesticides. Fertilizers are nutrient chemicals that enhance the growth of the plant. The important elements in the fertilizers are nitrogen, phosphorus and potassium. Nitrogen is usually in the form of ammonia, ammonium nitrate, ammonium sulphate, ammonium phosphate or solutions of these materials. Other nitrogen-containing chemicals are used for some special nutrient needs. Ammonium phosphate is the normal source of phosphorous. Potash (potassium oxide) is the potassium nutrient. Animal health products are any chemicals that are used to promote the health or growth of an animal. This includes products that are used topically by drenching or pouring-on, orally as a tablet or gel, and injectibles.
Pesticides
The most significant development in the pesticide manufacturing industry has been the introduction of the environmentally friendly pesticides. The imidazolinone family of herbicides has been a benefit to soybean and other field crops, as the herbicides are much more effective pound for pound; are less toxic to humans, animals and fish; have less persistence in the soil; and are formulated using water instead of flammable solvents, as compared to the old generation nitroaromatics. Concurrent with these innovations is the development of imidazolinones-resistant seeds that can be protected from weed growth. Corn is in the forefront in this area and has been successfully grown, protected by the imidazolinones. This also makes carry-over from year to year of the herbicide an insignificant problem, as in many areas soybeans and corn are rotated.
A newer development is the production of the synthetic pyrethroids, which are broad-range pesticides. These products are effective pesticides and are less toxic to animals and humans than the old organophosphates and carbamates. They are activated by the insect’s biological system and therefore not a danger to vertebrates. They are also less persistent in the environment, as they are biodegradable.
There have also been developments in the use of the old generation pesticides and herbicides. Herbicide formulations have been developed that utilize water dispersion technology that eliminates the use of volatile solvents. This not only reduces the amount of volatile organic chemicals that go to the atmosphere, but also makes handling, storage, formulation and transportation much safer. In the area of pesticides, a superior method of handling the toxic pesticides has been developed that uses closed container transfer of the material from the package to the spreader, called “Lock-N-Load”. This reduces the chances of exposure to these toxic materials. Organophosphates are still being used successfully to help eradicate health problems such as malaria and river blindness. Some of the less toxic organophosphates are effective in the treatment of animals for insects, worms and mites by direct application to the skin using pour-on or aerosol formulations.
The pesticide industry is regulated by many countries, and labelling, application to plants and soil, training in pesticide use, and transportation are controlled. Many pesticides can only be spread by licensed applicators. Precautions during pesticide application are discussed elsewhere in this Encyclopaedia. Bulk transportation vehicles can only be operated by qualified drivers. The producers of pesticide have a legal obligation to provide safe handling and application methods. This is usually accomplished by providing comprehensive labelling, training and material safety data sheets (MSDSs) (see the chapter Using, storing and transporting chemicals).
Another problem is the disposal of empty containers. It is not advisable, and in many places it is illegal, to reuse pesticide containers. Many advances have been made to mitigate this problem. Plastic containers have been collected by the distributors and reprocessed into plastic pipe. Bulk, refillable containers have been used. With the advent of the wettable powders and water-based dispersions, triple rinsing the container into the solutions tank gives the applicator a method to decontaminate the container before landfilling or recycling. Hand lances with spray nozzles that can pierce the container are used to assure proper cleaning and the destruction of the container so that it can not be reused.
Pesticides are made to kill; therefore, care is necessary to handle them safely. Some of the problems have been lessened by the product advances. In most cases, copious quantities of water are the best first-aid treatment for superficial exposures to skin and eyes. For ingestion, it is best to have a specific antidote available. It is important that the nearest health facility know what is being used and have a supply of the appropriate antidote on hand. For instance, organophosphates and carbamates cause cholinesterase inhibition. Atropine, the specific antidote for the treatment of this reaction, should be available wherever these pesticides are used.
For further discussion of pesticides, see the eponymous article in this chapter.
Fertilizers
Ammonia is the base of most important fertilizers. The major fertilizers are ammonia itself, ammonium nitrate, urea, ammonium sulphate and ammonium phosphate. There appears to be an environmental problem associated with nitrogen use, as the ground water in many farming areas is contaminated with nitrates, which causes health problems when the water is consumed as drinking water. There are pressures for farmers to use less fertilizer and to rotate crops of nitrogen-using legumes such as soy beans and rye grass. Ammonium nitrate, an oxidizer, is explosive if heated. The dangers of ammonium nitrate as a blasting agent were demonstrated by the destruction of a US federal building in Oklahoma City, Oklahoma, in 1995. There is some movement to add inert ingredients to make fertilizer-grade ammonium nitrate detonation-resistant. An industrial explosion resulting in multiple fatalities which occurred in an ammonium nitrate solutions plant that was thought to be safe from detonation because the ammonium nitrate was handled as an 85% solution is anonther example. Investigation results indicated that an intricate condition of temperature and contamination caused the incident. These conditions would not exist in the retail or farming sector. Anhydrous ammonia is a moderately toxic gas at room temperature and must be kept under pressure or refrigeration during storage and use. It is a skin, eye and respiratory irritant, can cause burns, and is flammable. It is directly applied to the soil or used as an aqueous solution. There is significant anhydrous ammonia storage in many farming areas. A hazardous condition is created if the storage is not managed correctly. This should include monitoring for leaks and emergency leak procedures.
Animal Health Products
The development and marketing of bovine somatotropin (BST) has caused controversy. BST, a fermentation product, raises the productivity of milk cows by 10 to 20%. Many people are opposed to the product because it introduces a chemical into the production of milk. However, the BST milk is indistinguishable from ordinary milk since BST is produced naturally by the milk cow. A problem seems to be an increase in infections of the cow’s udder. Antibiotics for these infections are available, but the use of these antibiotics is also controversial. The important benefits of BST are the increased production of milk with a reduction in food consumption and a similar reduction in cow manure, a material that is a solid-waste problem in many areas. A similar product, porcine somatotropin (PST), is still in the testing stage. It produces bigger hogs quickly, utilizing less feed, and results in pork containing less fat.
Antibiotic use in the beef-raising industry is also causing controversy. There is fear that consumption of large amounts of beef will result in hormonal problems in humans. There has been little in the way of confirmed problems, but the concern persists. Animal health products have been developed that control worms in animals. The previous generation was a synthetic chemical product, but the new generation products are the result of biological fermentation technology. These products are effective in many types of animals at very low use levels, and include domestic pets in their protection arena. These products are very toxic to aquatic life, though, so much care must be taken to avoid contamination of creeks and streams. These materials do biodegrade, so there appear to be no long-term or residual aquatic problems.
Manufacture of Agricultural Chemicals
The manufacturing of agricultural chemicals entails many processes and raw materials. Some agricultural chemicals are batch chemical syntheses that involve exothermic reactions where temperature control and emergency relief sizing are an issue. Hazard evaluations are necessary to assure that all the hazards are discovered and addressed. Hazard and operability studies (HAZOP) are recommended for conducting reviews. Relief sizing must be conducted using Design Institute for Emergency Relief Systems (DIERS) technology and data from calorimetric equipment. Usually, because of the complexity of the molecules, the production of agricultural chemicals involves many steps. Sometimes there is considerable aqueous and organic liquid waste. Some of the organics may be recyclable, but most of the aqueous waste must be biologically treated or incinerated. Both methods are difficult because of the presence of organic and inorganic salts. The previous generation herbicides, because they involved nitrations, were produced using continuous reactors to minimize the quantities of the nitrated materials at reaction temperatures. Severe runaway reactions, resulting in property damage and injuries, have occurred when batch reactors of nitrated organics have been subjected to a temperature excursion or contamination.
Many modern pesticide products are dry powders. If the concentration, particle size, oxygen concentration and a source of ignition are present at the same time, a dust explosion can occur. The use of inerting, the exclusion of oxygen, and utilization of nitrogen or carbon dioxide minimizes the oxygen source and can make the processes safer. These dusts may also be an industrial hygiene issue. Ventilation, both general and local, is a solutions to these problems.
The major fertilizers are made continuously rather than by the batch process. Ammonia is made by reforming methane at high temperatures utilizing a specific catalyst. Carbon dioxide and hydrogen are also formed and must be separated from the ammonia. Ammonium nitrate is made from ammonia and nitric acid in a continuous reactor. The nitric acid is formed by the continuous oxidation of ammonia on a catalytic surface. Ammonium phosphate is a reaction of ammonia and phosphoric acid. Phosphoric acid is made by reacting sulphuric acid with phosphate -containing ores. Sulphuric acid is formed by burning sulphur to sulphur dioxide, and catalytically converting the sulphur dioxide continuously to sulphur trioxide, and then adding water to form the sulphuric acid. Urea is a continuous high-pressure reaction of carbon dioxide and ammonia, the carbon dioxide usually coming from the ammonia continuous reaction by-product.
Many of these raw materials are toxic and volatile. Release of the raw materials or finished products, through an equipment failure or operator error, can expose employees and others in the community. A detailed emergency response plan is a necessary tool to minimize the effects of a release. This plan should be developed by determining a credible worst-case event through hazard evaluations and then forecasting consequences using dispersion modelling. This plan should include a method to notify employees and the community, an evacuation plan, emergency services and a recovery plan.
Transportation of agricultural chemicals should be thoroughly investigated to choose the safest route—one that minimizes the exposures if an incident occurs. A transportation emergency response plan should be implemented to address transportation incidents. This plan should include a published emergency response telephone number, company personnel to respond to calls and, in some cases, an accident site emergency response team.
Fermentation is the method of producing some of the animal health products. Fermentation is usually not a hazardous process, as it involves growing a culture using a nutritional medium such as lard oil, glucose, or starch. Sometimes anhydrous ammonia is used for pH (acidity) control or as a nutrient, so the process can involve hazards. Solvents may be used to extract the active cells, but the quantities and the methodology are such that is can be done safely. Recycling these solvents is often part of the process.
Adapted from 3rd edition, Encyclopaedia of Occupational Health and Safety. Revision includes information from A. Bruusgaard, L.L. Cash, Jr., G. Donatello, V. D’Onofrio, G. Fararone, M. Kleinfeld, M. Landwehr, A. Meiklejohn, J.A. Pendergrass, S.A. Roach, T.A. Roscina, N.I. Sadkovskaja and R. Stahl.
Minerals are used in ceramics, glass, jewellery, insulation, stone carving, abrasives, plastics and numerous other industries in which they present primarily an inhalation hazard. The amount and type of impurities within the minerals may also determine the potential hazard associated with inhalation of the dust. The major concern during mining and production is the presence of silica and asbestos. The silica content in different rock formations, such as sandstone, feldspars, granite and slate, may vary from 20% to nearly 100%. It is therefore imperative that worker exposure to dust concentrations be kept to a minimum by the implementation of strict dust-control measures.
Improved engineering controls, wet drilling, exhaust ventilation and remote handling are recommended to prevent the development of lung disease in mineral workers. Where effective engineering controls are not possible, workers should wear approved respiratory protection, including the proper selection of respirators. Where possible, industrial substitution of less hazardous agents can reduce occupational exposure. Finally, the education of workers and employers regarding the hazards and proper control measures is an essential component of any prevention programme.
Regular medical examinations of mineral-dust-exposed workers should include evaluations for respiratory symptoms, lung function abnormalities and neoplastic disease. Workers showing the first signs of lung changes should be assigned to other jobs entailing no dust hazards. In addition to individual reports of illness, data from groups of workers should be collected for prevention programmes. The chapter Respiratory system provides more detail on the health effects of several of the minerals described here.
Apatite (Calcium Phosphate)
Occurrence and uses. Apatite is a natural calcium phosphate, usually containing fluorine. It occurs in the earth’s crust as phosphate rock, and it is also the chief component of the bony structure of teeth. Deposits of apatite are located in Canada, Europe, the Russian Federation and the United States.
Apatite is used in laser crystals and as a source of phosphorus and phosphoric acid. It is also employed in the manufacture of fertilizers.
Health hazards. Skin contact, inhalation or ingestion may cause irritation of skin, eyes, nose, throat or gastric system. Fluorine may be present in the dust and may cause toxic effects.
Asbestos
Occurrence and uses. Asbestos is a term used to describe a group of naturally occurring fibrous minerals which are widely distributed throughout the world. The asbestos minerals fall into two groups—the serpentine group, which includes chrysotile, and the amphiboles, which include crocidolite, tremolite, amosite and anthophyllite. Chrysotile and the various amphibole asbestos minerals differ in crystalline structure, in chemical and surface characteristics, and in the physical characteristics of their fibres.
The industrial features which have made asbestos so useful in the past are the high tensile strength and flexibility of the fibres, and their resistance to heat and abrasion and to many chemicals. There are many manufactured products which contain asbestos, including construction products, friction materials, felts, packings and gaskets, floor tiles, paper, insulation and textiles.
Health hazards. Asbestosis, asbestos-related pleural disease, malignant mesothelioma and lung cancer are specific diseases associated with exposure to asbestos dust. The fibrotic changes which characterize the pneumoconiosis, asbestosis, are the consequence of an inflammatory process set up by fibres retained in the lung. Asbestos is discussed in the chapter Respiratory system.
Bauxite
Occurrence and uses. Bauxite is the principal source of aluminium. It consists of a mixture of minerals formed by the weathering of aluminium-bearing rocks. Bauxites are the richest form of these weathered ores, containing up to 55% alumina. Some lateritic ores (containing higher percentages of iron) contain up to 35% Al2O3. The commercial deposits of bauxite are mainly gibbsite (Al2O3 3H2O) and boehmite (Al2O3 H2O), and are found in Australia, Brazil, France, Ghana, Guinea, Guyana, Hungary, Jamaica and Surinam. Gibbsite is more readily soluble in sodium hydroxide solutions than boehmite, and is therefore preferred for alumina production.
Bauxite is extracted by open-cast mining. The richer ores are used as mined. The lower-grade ores may be upgraded by crushing and washing to remove clay and silica waste.
Health hazards. Severe pulmonary disability has been reported in workers employed on smelting bauxite that is combined with coke, iron and very small amounts of silica. The affliction is known as “Shaver’s disease”. Because silica contamination of aluminium-containing ores is common, the health hazards associated with the presence of free crystalline silica in bauxite ores must be considered an important causal factor.
Clays (Hydrated Aluminium Silicates)
Occurrence and uses. Clay is a malleable plastic material formed by the weathered disintegration residues of argillaceous silicate rock; it usually contains 15 to 20% water and is hygroscopic. It occurs as a sediment in many geological formations in all parts of the world and contains in varying amounts feldspars, mica and admixtures of quartz, calcspar and iron oxide.
The quality of clay depends on the amount of alumina in it—for example, a good porcelain clay contains about 40% alumina, and the silica content is as low as 3 to 6%. On average the quartz content of clay deposits is between 10 and 20%, but at worst, where there is less alumina than usual, the quartz content may be as high as 50%. Content may vary in a deposit, and separation of grades may take place in the pit. In its plastic state, clay can be moulded or pressed, but when fired it becomes hard and retains the shape into which it has been formed.
Clay is often extracted in open-cast pits but sometimes in underground mines. In open-cast pits the method of extraction depends on the quality of the material and the depth of the deposit; sometimes the conditions require the use of hand-operated pneumatic tools, but, wherever possible, mining is mechanized, using excavators, power shovels, clay cutters, deep digging machines and so on. The clay is taken to the surface by truck or cable transport. The clay brought to the surface may be subjected to preliminary processing before dispatch (drying, crushing, pugging, mixing and so on) or it may be sold whole (see the chapter Mining and quarrying). Sometimes, as in many brickyards, the clay pit may be adjacent to the factory where the finished articles are made.
Different types of clay form the basic material in the manufacture of pottery, bricks and tiles, and refractories. Clay may be used without any processing in dam construction; in situ, it sometimes serves as a cover for gas stored in lower stratum. Appropriate ventilation and engineering controls are required.
Health hazards. Clays usually contain large amounts of free silica, and chronic inhalation can cause silicosis. Skin contact with wet clay may cause skin drying and irritation. There is a silicosis risk to underground workers where there is mechanized mining of clay with a high quartz content and little natural moisture. Here the decisive factor is not merely the quartz content but also the natural dampness: if the moisture level is less than 12%, much fine dust must be expected in mechanical extraction.
Coal
Occurrence and uses. Coal is a natural, solid, combustible material formed from prehistoric plant life. It occurs in layers or veins in sedimentary rocks. Conditions suitable for the natural formation of coal occurred between 40 and 60 million years ago in the Tertiary Age (brown-coal formation) and over 250 million years ago in the Carboniferous Age (bituminous-coal formation), when swampland forests thrived in a hot climate and then gradually subsided during ensuing geological movements. The main deposits of brown coal are found in Australia, eastern Europe, Germany, the Russian Federation and the United States. Major reserves of bituminous coal are located in Australia, China, India, Japan, the Russian Federation and the United States.
Coal is an important source of chemical raw materials. Pyrolysis or destructive distillation yields coal tar and hydrocarbon gases, which can be upgraded by hydrogenation or methanation to synthetic crude oil and fuel gas. Catalytic hydrogenation yields hydrocarbon oils and gasoline. Gasification produces carbon monoxide and hydrogen (synthetic gas), from which ammonia and other products can be made. While in 1900, 94% of the world’s energy requirements were met by coal and only 5% by petroleum and natural gas, coal has been increasingly replaced by liquid and gaseous fuels throughout the world.
Health hazards. Hazards of mining and of coal dust are discussed in the chapters Mining and quarrying and Respiratory system.
Corundum (Aluminium Oxide)
Occurrence and uses. Corundum is one of the principal natural abrasives. Natural corundum and artificial corundum (alundum or artificial emery) are usually relatively pure. The artificial material is produced from bauxite by smelting in an electric furnace. Because of its hardness, corundum is used to shape metals, wood, glass and ceramics, by a process of grinding or polishing. Health hazards are discussed elsewhere in this Encyclopaedia.
Diatomaceous Earth (Diatomite, Kieselguhr, Infusorial Earth)
Occurrence and uses. Diatomaceous earth is a soft, bulky material composed of skeletons of small, prehistoric aquatic plants related to algae (diatoms). Certain deposits comprise up to 90% free amorphous silica. They have intricate geometric forms and are available as light-coloured blocks, bricks, powder and so on. Diatomaceous earth absorbs 1.5 to 4 times its weight of water and has a high oil absorption capacity. Deposits occur in Algeria, Europe, the Russian Federation and the western United States. Diatomaceous earth may be used in foundries, in paper coating, in ceramics and in the maintenance of filters, abrasives, lubricants and explosives. It is used as a filtering medium in the chemical industry. Diatomaceous earth also finds use as a drilling-mud thickener; an extender in paints, rubber and plastic products; and as an anti-caking agent in fertilizers.
Health hazards. Diatomaceous earth is highly respirable. For many industrial purposes diatomaceous earth is calcined at 800 to 1,000 ºC to produce a greyish-white powder called kieselguhr, which may contain 60% or more crystobalite. During mining and processing of diatomaceous earth, the risk of death from both respiratory diseases and lung cancer has been related to the inhalation of dust as well as to cumulative crystalline silica exposures, as discussed in the chapter Respiratory system.
Erionite
Occurrence and uses. Erionite is a crystalline, fibrous zeolite. Zeolites, a group of alumino-silicates found in the cavities of volcanic rocks, are used in the filtration of hard water and in the refining of oil. Erionite occurs in California, Nevada and Oregon in the United States, and in Ireland, Iceland, New Zealand and Japan.
Health hazards. Erionite is a known human carcinogen. Chronic inhalation may cause mesothelioma.
Feldspar
Occurrence and uses. Feldspar is a general name for a group of sodium, potassium, calcium and barium aluminium silicates. Commercially, feldspar usually refers to the potassium feldspars with the formula KAlSi3O8, usually with a little sodium. Feldspar occurs in the United States. It is used in pottery, enamel and ceramic ware, glass, soaps, abrasives, cements and concretes. Feldspar serves as a bond for abrasive wheels, and it finds use in insulating compositions, tarred roofing materials and fertilizers.
Health hazards. Chronic inhalation may cause silicosis due to the presence of substantial amounts of free silica. Feldspars may also contain irritating sodium oxide (soda spars), potassium oxide (potash spars), and calcium oxide (lime spars) in insoluble form. See the section “Silica” below.
Flint
Occurrence and uses. Flint is a crystalline form of native silica or quartz. It occurs in Europe and the United States. Flint is used as an abrasive, a paint extender and a filler for fertilizer. In addition, it finds use in insecticides, rubber, plastics, road asphalt, ceramics and chemical tower packing. Historically, flint has been an important mineral because it was used to make some of the first known tools and weapons.
Health hazards are related to the toxic properties of silica.
Fluorspar (Calcium Fluoride)
Occurrence and uses. Fluorspar is a mineral that contains 90 to 95% calcium fluoride and 3.5 to 8% silica. It is extracted by drilling and blasting. Fluorspar is a principal source of fluorine and its compounds. It is used as a flux in open hearth steel furnaces and in metal smelting. In addition, it finds use in the ceramics, paint and optical industries.
Health hazards. The hazards of fluorspar are due primarily to the harmful effects of the fluorine content and its silica content. Acute inhalation may cause gastric, intestinal, circulatory and nervous system problems. Chronic inhalation or ingestion may cause loss of weight and appetite, anaemia, and bone and teeth defects. Pulmonary lesions have been reported among persons inhaling dust containing 92 to 96% calcium fluoride and 3.5% silica. It appears that calcium fluoride intensifies the fibrogenic action of silica in the lungs. Cases of bronchitis and silicosis have been reported among fluorspar miners.
In the mining of fluorspar, dust control should be carefully enforced, including wet drilling, watering of loose rock, and exhaust and general ventilation. When heating fluorspar, there is also the hazard of hydrofluoric acid being formed, and the relevant safety measures should be applied.
Granite
Occurrence and uses. The coarse-grained igneous rock granite consists of quartz, feldspar and mica in shapeless interlocking grains. It finds use as crushed granite and as dimension granite. After it is crushed to the required size, granite may be used for concrete aggregate, road metal, railroad ballast, in filter beds, and for riprap (large chunks) in piers and breakwaters. The colors—pink, grey, salmon, red and white—are desirable for dimension granite. The hardness, uniform texture and other physical properties make dimension granite ideal for monuments, memorials, foundation blocks, steps and columns.
Large production of crushed granite comes mainly from California, with substantial amounts from the other US States of Georgia, North Carolina, South Carolina and Virginia. Major production areas of dimension granite in the United States include Georgia, Maine, Massachusetts, Minnesota, North Carolina, South Dakota, Vermont, and Wisconsin.
Health hazards. Granite is heavily contaminated with silica. Therefore, silicosis is a major health hazard in granite mining.
Graphite
Occurrence and uses. Graphite is found in almost every country of the world, but the majority of production of the natural ore is limited to Austria, Germany, Madagascar, Mexico, Norway, the Russian Federation and Sri Lanka. Most, if not all, natural graphite ores contain crystalline silica and silicates.
Lump graphite is found in veins which cross different types of igneous and metamorphic rock containing mineral impurities of feldspar, quartz, mica, pyroxine, zircon, rutile, apatite and iron sulphides. The impurities are often in isolated pockets in the veins of ore. Mining is commonly underground, with hand drills for selective mining of narrow veins.
Deposits of amorphous graphite are also underground, but usually in much thicker beds than the veins of lumps. Amorphous graphite is commonly associated with sandstone, slate, shale, limestone and adjunct minerals of quartz and iron sulphides. The ore is drilled, blasted and hand-loaded into wagons and brought to the surface for grinding and impurity separation.
Flake graphite is usually associated with metamorphosed sedimentary rock such as gneiss, schists and marbles. The deposits are often on or near the surface. Consequently, normal excavating equipment such as shovels, bulldozers and scarifiers are used in open-cast mining, and a minimum of drilling and blasting is necessary.
Artificial graphite is produced by the heating of coal or petroleum coke, and generally contains no free silica. Natural graphite is used in the manufacture of foundry linings, lubricants, paints, electrodes, dry batteries and crucibles for metallurgical purposes. The “lead” in pencils is also graphite.
Health hazards. Inhalation of carbon, as well as associated dusts, may occur during the mining and milling of natural graphite, and during the manufacture of artificial graphite. X-ray examinations of natural and artificial graphite workers have shown varying classifications of pneumoconioses. Microscopic histopathology has revealed pigment aggregates, focal emphysema, collagenous fibrosis, small fibrous nodules, cysts and cavities. The cavities have been found to contain an inky fluid in which graphite crystals were identified. Recent reports note that the materials implicated in exposures leading to severe cases with massive pulmonary fibrosis are likely to be mixed dusts.
Graphite pneumoconiosis is progressive even after the worker has been removed from the contaminated environment. Workers may remain asymptomatic during many years of exposure, and disability often comes suddenly. It is essential that periodic analyses are made of the raw ore and airborne dust for crystalline silica and silicates, with special attention to feldspar, talc and mica. Acceptable dust levels must be adjusted to accommodate the effect these disease-potentiating dusts may have on workers’ health.
In addition to being exposed to the physical hazards of mining, graphite workers may also face chemical hazards, such as hydrofluoric acid and sodium hydroxide used in graphite purification. Protection against the risks associated with these chemicals should be part of any health programme.
Gypsum (Hydrated Calcium Sulphate)
Occurrence and uses. Though it occurs throughout the world, gypsum is rarely found pure. Gypsum deposits may contain quartz, pyrites, carbonates and clayey and bituminous materials. It occurs in nature in five varieties: gypsum rock, gypsite (an impure, earthy form), alabaster (a massive, fine-grained translucent variety), satin spar (a fibrous silky form) and selenite (transparent crystals).
Gypsum rock may be crushed and ground for use in the dihydrate form, calcined at 190 to 200 ºC (thus removing part of the water of crystallization) to produce calcium sulphate hemihydrate or plaster of Paris, or completely dehydrated by calcining at over 600 ºC to produce anhydrous or dead-burned gypsum.
Ground dihydrate gypsum is used in the manufacture of Portland cement and artificial marble products; as a soil conditioner in agriculture; as a white pigment, filler or glaze in paints, enamels, pharmaceuticals, paper and so on; and as a filtration agent.
Health hazards. Workers employed in the processing of gypsum rock may be exposed to high atmospheric concentrations of gypsum dust, furnace gases and smoke. In gypsum calcining, workers are exposed to high environmental temperatures, and there is also the hazard of burns. Crushing, grinding, conveying and packaging equipment presents a danger of machinery accidents. The pneumoconiosis observed in gypsum miners has been attributed to silica contamination.
Dust formation in gypsum processing should be controlled by mechanization of dusty operations (crushing, loading, conveying and so on), addition of up to 2% by volume of water to gypsum prior to crushing, use of pneumatic conveyors with covers and dust traps, enclosure of dust sources and provision of exhaust systems for kiln openings and for conveyor transfer points. In the workshops containing the calcining kilns, it is advisable to face the walls and floors with smooth materials to facilitate cleaning. Hot piping, kiln walls and drier enclosures should be lagged to reduce the danger of burns and to limit heat radiation to the work environment.
Limestone
Occurrence and uses. Limestone is a sedimentary rock composed mainly of calcium carbonate in the form of mineral calcite. Limestones may be classified either according to the impurities they contain (dolomitic limestone, which contains substantial amounts of magnesium carbonate; argillaceous limestone, with a high clay content; siliceous limestone, which contains sand or quartz; and so on) or according to the formation in which they occur (e.g., marble, which is a crystalline limestone). Limestone deposits are widely distributed throughout the earth’s crust and are extracted by quarrying.
Since early times, limestone has been used as a building stone. It is also crushed for use as a flux in smelting, in refining, and for the manufacture of lime. Limestone is used as hardcore and ballast in road and railway construction, and it is mixed with clay for the manufacture of cement.
Health hazards. During extraction, the appropriate quarrying safety measures should be taken, and machinery-guarding principles should be observed on crushers. The main health hazard in limestone quarries is the possible presence, in the airborne limestone dust, of free silica, which normally accounts for 1 to 10% of limestone rock. In studies of limestone quarry and processing workers, x-ray examinations revealed pulmonary changes, and clinical examination showed pharyngitis, bronchitis and emphysema. Workers dressing stone for construction work should observe the safety measures appropriate to the stone industry.
Marble (Calcium Carbonate)
Occurrence and uses. Marble is geologically defined as a metamorphosed (re-crystallized) limestone composed primarily of crystalline grains of calcite, dolomite, or both, having a visible crystalline texture. Long usage of the term marble by the quarry and finishing industry has led to the development of the term commercial marble, which includes all crystalline rock capable of taking a polish and composed primarily of one or more of the following minerals: calcite, dolomite or serpentine.
Marble has been utilized throughout historic time as an important construction material because of its strength, durability, ease of workability, architectural adaptability and aesthetic satisfaction. The marble industry comprises two major branches—dimension marble and crushed and broken marble. The term dimension marble is applied to deposits of marble quarried for the purpose of obtaining blocks or slabs that meet specifications as to size and shape. The uses of dimension marble include building stone, monumental stone, ashlar, veneer panelling, wainscotting, tiling, statuary and so on. Crushed and broken marble ranges in size from large boulders to finely ground products, and products include aggregates, ballast, roofing granules, terrazzo chips, extenders, pigments, agricultural lime and so on.
Health hazards. Occupational diseases specifically connected with the mining, quarrying and processing of marble itself have not been described. In underground mining there may be exposure to toxic gases produced by blasting and some types of motor-driven equipment; adequate ventilation and respiratory protection are necessary. In abrasive blasting there will be exposure to silica if sand is used, but silicon carbide or aluminium oxide are equally effective, carry no silicosis risk, and should be substituted. The large quantities of dust generated in processing marble should be subject to dust control, either by the use of moist methods or by exhaust ventilation.
Mica
Occurrence and uses. Mica (from the Latin micare, to gleam or sparkle) is a mineral silicate which occurs as a primary constituent of igneous rocks, particularly granites. It is also a common component of such silicate materials as kaolin, which are produced by the weathering of these rocks. In the rock bodies, particularly in the pegmatite veins, mica occurs as lenticular masses of cleavable sheets (known as books) of up to 1 m in diameter, or as particles. There are many varieties, of which the most useful are muscovite (common, clear or white mica), phlogopite (amber mica), vermiculite, lepidolite and sericite. Muscovite is generally found in siliceous rocks; there are substantial deposits in India, South Africa and the United States. Sericite is the small plate variety of muscovite. It results from the weathering of schists and gneisses. Phlogopite, which occurs in calcareous rocks, is concentrated in Madagascar. Vermiculite has the outstanding characteristic of expanding considerably when quickly heated to around 300 ºC. There are large deposits in the United States. The main value of lepidolite lies in its high content of lithium and rubidium.
Mica is still used for slow-combustion stoves, lanterns or peep-holes of furnaces. The supreme quality of mica is that it is dielectric, which makes it a top-priority material in aircraft construction. Mica powder is used in the manufacture of electric cables, pneumatic tyres, welding electrodes, bituminized cardboard, paints and plastics, dry lubricants, dielectric dressings and flameproof insulators. It is often compacted with alkyd resins. Vermiculite is widely used as an insulating material in the building industry. Lepidolite is used in the glass and ceramic industries.
Health hazards. When working with mica, the generation of static electricity is possible. Straightforward engineering techniques can harmlessly discharge it. Mica miners are exposed to the inhalation of a wide variety of dusts, including quartz, feldspar and silicates. Chronic inhalation may cause silicosis. Exposure of workers to mica powder may cause irritation of the respiratory tract, and, after several years, nodular fibrotic pneumoconiosis can occur. It was long considered to be a form of silicosis, but it is now believed not to be, because pure mica dust contains no free silica. The radiological appearance is often close to that of asbestosis. Experimentally, mica has proved to possess a low cytotoxicity on macrophages and to induce only a poor fibrogenic response limited to the formation of thick reticulin fibres.
Chronic inhalation of vermiculite, which often contains asbestos, may cause asbestosis, lung cancer and mesothelioma. Ingestion of vermiculite is also suspected in stomach and intestinal cancer.
Pumice
Occurrence and uses. Pumice is a porous rock, grey or white, fragile and of low specific gravity, coming from recent volcanic magma; it is composed of quartz and silicates (mainly feldspar). It is found either pure or mixed with various substances, chief among them obsidian, which differs by its shiny black colour and its specific gravity, which is four times greater. It occurs principally in Ethiopia, Germany, Hungary, Italy (Sicily, Lipari), Madagascar, Spain and the United States. Some varieties, such as Lipari pumice, have a high content of total silica (71.2 to 73.7%) and a fair amount of free silica (1.2 to 5%).
In commerce and for practical uses, a distinction is made between pumice in blocks and in powder. When it is in block form the designation differs according to the size of block, colour, porosity and so on. The powder form is classified by numbers according to grain size. Industrial processing comprises a number of operations: sorting to separate the obsidian, crushing and pulverizing in machines with stone or metal grinding wheels, drying in open kilns, sifting and screening using hand-operated flat and open sieves and reciprocating or rotating screens, the waste matter generally being recovered.
Pumice is used as an abrasive (block or powder), as a lightweight building material, and in the manufacture of stoneware, explosives and so on.
Health hazards. The most dangerous operations involving exposure to pumice are kiln drying and sifting, because of the large amount of dust produced. Apart from the characteristic signs of silicosis observed in the lungs and sclerosis of the hilar lymphatic glands, the study of some fatal cases has revealed damage to various sections of the pulmonary arterial tree. Clinical examination has revealed respiratory disorders (emphysema and sometimes pleural damage), cardiovascular disorders (cor pulmonale) and renal disorders (albuminuria, haematuria, cylindruria), as well as signs of adrenal deficiency. Radiological evidence of aortitis is more common and serious than in the case of silicosis. A typical radiological appearance of lungs in liparitosis is the presence of linear thickening due to lamellar atelactasis.
Sandstone
Occurrence and uses. Sandstone is a siliciclastic sedimentary rock consisting primarily of sand, usually sand that is predominantly quartz. Sandstones often are poorly cemented and can be easily crumbled into sand. Yet, strong, durable sandstone, with tan and grey colours, is used as dimension sandstone for exterior facing and trim for buildings, in houses, as curbstones, in bridge abutments and in various retaining walls. Firm sandstones are crushed for use as concrete aggregate, railroad ballast and riprap. However, many commercial sandstones are weakly cemented and therefore are crumbled and used for moulding sand and glass sand. Glass sand is the main ingredient in glass. In the metalworking industry, sand with good cohesiveness and refractoriness is used for making special shaped moulds into which molten metal is poured.
Sandstone is found throughout the United States, in Illinois, Iowa, Minnesota, Missouri, New York, Ohio, Virginia and Wisconsin.
Health hazards. The primary risks are from the silica exposure, which is discussed in the chapter Respiratory system.
Silica
Occurrence and uses. Silica occurs naturally in crystalline (quartz, cristobalite and tridymite), cryptocrystalline (e.g., chalcedony) and amorphous (e.g., opal) forms, and the specific gravity and melting point depend on the crystalline form.
Crystalline silica is the most widely occurring of all minerals, and it is found in most rocks. The most commonly occurring form of silica is the sand found on beaches throughout the world. The sedimentary rock sandstone consists of grains of quartz cemented together with clays.
Silica is a constituent of common glass and most refractory bricks. It is also used extensively in the ceramic industry. Rocks containing silica are used as common building materials.
Free and combined silica. Free silica is silica which is not combined with any other element or compound. The term free is used to distinguish it from combined silica. Quartz is an example of free silica. The term combined silica originates from the chemical analysis of naturally occurring rocks, clays and soils. The inorganic constituents are found to consist almost always of oxides bound chemically, commonly including silicon dioxide. Silica so combined with one or more other oxides is known as combined silica. The silica in mica, for example, is present in the combined state.
In crystalline silica, the silicon and oxygen atoms are arranged in a definite, regular pattern throughout the crystal. The characteristic crystal faces of a crystalline form of silica are the outward expression of this regular arrangement of atoms. The crystalline forms of free silica are quartz, cristobalite and tridymite. Quartz is crystallized in the hexagonal system, cristobalite in the cubic or tetragonal system and tridymite in the ortho-rhombic system. Quartz is colourless and transparent in the pure form. The colours in naturally occurring quartz are due to contamination.
In amorphous silica the different molecules are in a dissimilar spatial relationship one to another, with the result that there is no definite regular pattern between molecules some distance apart. This absence of long-range order is characteristic of amorphous materials. Cryptocrystalline silica is intermediate between crystalline and amorphous silica in that it consists of minute crystals or crystallites of silica which are themselves arranged in no regular orientation one to another.
Opal is an amorphous variety of silica with a varying amount of combined water. A commercially important form of amorphous silica is diatomaceous earth, and calcinated diatomaceous earth (kieselguhr). Chalcedony is a cryptocrystalline form of silica which occurs filling cavities in lavas or associated with flint. It is also found in the annealing of ceramics when, under certain temperature conditions, the quartz in silicates may crystallize out in minute crystals in the body of the ware.
Health hazards. The inhalation of airborne dust of silica gives rise to silicosis, a serious and potentially fatal fibrotic disease of the lungs. The chronic, accelerated, and acute forms of silicosis reflect differing exposure intensities, latency periods and natural histories. Chronic silicosis may progress to progressive massive fibrosis, even after exposure to silica-containing dust has ceased. Hazards of silica are discussed in more detail in the chapter Respiratory system.
Slate
Occurrence and uses. Slate is very fine-grained, sedimentary argillaceous or schisto-argillaceous rock, easily split, of a leaden-grey, reddish or greenish colour. The principal deposits are in France (Ardennes), Belgium, the United Kingdom (Wales, Cornwall), the United States (Pennsylvania, Maryland) and Italy (Liguria). With a high calcium carbonate content, they contain silicates (mica, chlorite, hydrosilicates), iron oxides and free silica, amorphous or crystalline (quartz). The quartz content of hard slates is in the region of 15%, and that of soft slates, less than 10%. In North Wales quarries, respirable slate dust contains between 13 and 32% of respirable quartz.
Slate slabs are used for roofing; stair treads; door, window and porch casements; flooring; fireplaces; billiard tables; electricity switch panels; and school blackboards. Powdered slate has been used as a filler or pigment in rustproofing or insulating paints, in mastics, and in paints and bituminous products for road surfacing.
Health hazards. Disease in slate workers has attracted attention since the early nineteenth century, and cases of “miner’s phthisis” uncomplicated by tubercle bacilli were described at an early date. Pneumoconiosis has been found in a third of workers studied in the slate industry in North Wales, and in 54% of slate pencil makers in India. Slateworkers’ pneumoconiosis may have features of silicosis due to the high quartz content of some slates. Chronic bronchitis and emphysema are frequently observed, especially in extraction workers.
The replacement of the hand pick by low-velocity mechanical equipment considerably reduces dust generation in slate quarries, and the use of local exhaust ventilation systems makes it possible to maintain airborne dust concentrations within acceptable limits for 8-hour exposure. Ventilation of underground workings, drainage of groundwater into pits, lighting and work organization are improving the general hygiene of working conditions.
Circular sawing should be carried out under water jets, but planing does not usually give rise to dust provided the slivers of slate are not allowed to fall to the ground. Larger sheets are usually wet-polished; however, where dry-polishing is carried out, well-designed exhaust ventilation should be employed since slate dust is not easily collected even when using scrubbers. The dust readily clogs bag filters.
Workshops should be cleaned daily to prevent accumulation of dust deposits; in certain cases, it may be preferable to prevent deposited dust in gangways from becoming airborne again by covering dust with sawdust rather than by wetting it.
Talc
Occurrence and uses. Talc is a hydrous magnesium silicate whose basic formula is (Mg Fe+2)3Si4O10 (OH2), with theoretical weight percentages as follows: 63% SiO2, 32% MgO and 5% H2O. Talc is found in a variety of forms and is frequently contaminated with other minerals, including silica and asbestos. Talc production occurs in Australia, Austria, China, France and the United States.
The texture, stability and fibrous or flaky properties of the various talcs have made them useful for many purposes. The purest grades (i.e., those which most nearly approximate the theoretical composition) are fine in texture and colour, and are therefore widely used in cosmetics and toilet preparations. Other varieties, containing admixtures of different silicates, carbonates and oxides, and perhaps free silica, are relatively coarse in texture and are used in the manufacture of paint, ceramics, automobile tyres and paper.
Health hazards. Chronic inhalation may cause silicosis if silica is present, or asbestosis, lung cancer, and mesothelioma if asbestos or asbestos-like minerals are present. Investigations of workers exposed to talc without associated asbestos fibres revealed trends for higher mortality from silicosis, silicotuberculosis, emphysema and pneumonia. The major clinical symptoms and signs of talc pneumoconiosis include chronic productive cough, progressive shortness of breath, diminished breath sounds, limited chest expansion, diffuse rales and clubbing of the finger tips. Lung pathology has revealed various forms of pulmonary fibrosis.
Wollastonite (Calcium Silicate)
Occurrence and uses. Wollastonite (CaSiO3) is a natural calcium silicate found in metamorphic rock. It occurs in many different forms in New York and California in the United States, in Canada, Germany, Romania, Ireland, Italy, Japan, Madagascar, Mexico, Norway and Sweden.
Wollastonite is used in ceramics, welding-rod coatings, silica gels, mineral wool and paper coating. It is also used as a paint extender, a soil conditioner, and as a filler in plastics, rubber, cements and wallboard.
Health hazards. Wollastonite dust may cause skin, eye and respiratory irritation.
GESTIS, the hazardous substance information system of the Berufsgenossenschaften (BG, statutory accident insurance carriers) in Germany, is presented here as a case study of an integrated information system for the prevention of risks from workplace chemical substances and products.
With the enactment and application of the regulation on hazardous substances in Germany in the mid-1980s, there was a huge increase in demand for data and information on hazardous substances. This demand had to be met directly by the BG within the framework of their industrial advisory and supervisory activities.
Specialists, including persons working with technical inspection services of the BG, workplace safety engineers, occupational physicians and those cooperating with expert panels, require specific health data. However, information regarding chemical hazards and the necessary safety measures is no less important for the layperson working with hazardous products. In the factory the effectiveness of work protection rules is what finally counts; it is therefore essential that relevant information be easily accessible to the factory owner, safety personnel, workers and, if appropriate, the work committees.
Against this background GESTIS was set up in 1987. Individual BG institutions had maintained databases mostly for more than 20 years. Within the framework of GESTIS, these databases were combined and supplemented with new components, including a “fact” database on substances and products, and information systems specific to particular branches of industry. GESTIS is organized on a central and peripheral basis, with comprehensive data for and about industry in Germany. It is arranged and classified according to branches of industry.
GESTIS consists of four core databases located centrally with the Berufsgenossenschaften Association and their Institute for Occupational Safety (BIA), plus peripheral, branch-specific information systems and documentation on occupational medicine surveillance and interfaces with external databases.
The target groups for hazardous substance information, such as safety engineers and occupational physicians, require different forms and specific data for their work. The form of information directed towards employees should be understandable and related to the specific handling of substances. Technical inspectors may require other information. Finally, the general public has a right to and an interest in workplace health information, including the identification and status of particular risks and the incidence of occupational disease.
GESTIS must be able to satisfy the information needs of various target groups by providing accurate information that focuses on practice.
Which data and information are needed?
Core information on substances and products
Hard facts must be the primary foundation. In essence these are facts about pure chemical substances, based on scientific knowledge and legal requirements. The scope of the subjects and information in safety data sheets, as, for example, defined by the European Union in EU Directive 91/155/EEC, correspond to the requirements of work protection in the factory and provide a suitable framework.
These data are found in the GESTIS central substance and product database (ZeSP), an online database compiled since 1987, with an emphasis on substances and in cooperation with the governmental labour inspection services (i.e., the hazardous substance databases of the states). The corresponding facts on products (mixtures) are established only on the basis of valid data on substances. In practice, a large problem exists because producers of safety data sheets often do not identify the relevant substances in preparations. The above-mentioned EU directive provides for improvements in the safety data sheets and requires more precise data on the listing of components (depending on the concentration levels).
The compilation of safety data sheets within GESTIS is indispensable for combining the producer data with substance data that are independent of the producers. This result occurs both through the branch-specific recording activities of the BG and through a project in cooperation with producers, who ensure that the safety data sheets are available, up-to-date and largely in data-processed form (see figure 1) in the ISI database (Information System Safety datasheets).
Figure 1.Collection and information centre for safety data sheets - basic structure
Because safety data sheets often do not adequately consider the special use of a product, specialists in branches of industry compile information on product groups (e.g., cooling lubricants for practical work protection in the factory) from producers’ information and substance data. Product groups are defined according to their use and their chemical risk potential. The information made available on product groups is independent of the data provided by producers on the composition of individual products because it is based on general formulae of composition. Thus, the user has access to a supplementary independent information source in addition to the safety data sheet.
A characteristic feature of ZeSP is the provision of information on the safe handling of hazardous substances in the workplace, including specific emergency and preventive measures. Furthermore, ZeSP contains comprehensive information on occupational medicine in a detailed, understandable and practice-related form (Engelhard et al. 1994).
In addition to the practice-oriented information outlined above, further data are needed in connection with national and international expert panels in order to undertake risk assessments for chemical substances (e.g., the EU Existing Chemicals Regulation).
For the evaluation of risk, data are required for the handling of hazardous substances, including (1) the use category of substances or products; (2) the amounts used in production and handling, and the number of persons working with or exposed to the hazardous substance or product; and (3) exposure data. These data can be obtained from hazardous substance registers at the factory level, which are obligatory under European hazardous substance law, for pooling at a higher level to form branch or general trade registers. These registers are becoming increasingly indispensable for providing the required background for political decision- makers.
Exposure data
Exposure data (i.e., measurement values of hazardous substance concentrations) are obtained through the BG within the framework of the BG measurement system for hazardous substances (BGMG 1993), to carry out compliance measurements in view of threshold values in the workplace. Their documentation is necessary for considering the level of technology when establishing threshold values and for risk analyses (e.g., in connection with the determination of risks in existing substances), for epidemiological studies and for evaluating occupational diseases.
The measurement values determined as part of workplace surveillance are therefore documented in the Documentation for Measurement Data on Hazardous Substances in the Workplace (DOK-MEGA). Since 1972 more than 800,000 measurement values have become available from over 30,000 firms. At present about 60,000 of these values are being added annually. Particular features of the BGMG include a quality assurance system, education and training components, standardized procedures for sampling and analysis, a harmonized measurement strategy on a legal basis and tools supported by data processing for information gathering, quality assurance and evaluation (figure 2).
Figure 2. BG measurement system for hazardous substances (BGMG) —cooperation between the BIA and the BG.
Exposure measurement values must be representative, repeatable and compatible. Exposure data from workplace surveillance in the BGMG are viewed strictly as “representative” of the individual factory situation, since the selection of measurement sites is carried out according to technical criteria in individual cases, not in accordance with statistical criteria. The question of representativeness arises, however, when measurement values for the same or a similar workplace, or even for entire branches of industry, have to be pooled statistically. Measurement data determined as part of surveillance activity generally give higher average values than data that have initially been collected to obtain a representative cross-section of a branch of industry.
For each measurement, differentiated recording and documentation of the relevant factory, process and sampling parameters are required so that the measured values can be combined in a way that is statistically reasonable, and evaluated and interpreted in a technically adequate manner.
In DOK-MEGA this goal is achieved on the following bases of data recording and documentation:
The BIA makes use of its experience with DOK-MEGA in a EU research project with representatives of other national exposure databases with the aim of improving the comparability of exposure and measurement results. In particular, an attempt is being made here to define core information as a basis for comparability and to develop a “protocol” for data documentation.
Health data
In addition to facts about chemical substances and products and about the results of exposure measurements, information is needed on the health effects of actual exposure to hazardous substances in the workplace. Adequate conclusions concerning occupational safety on and beyond the corporate level can be drawn only from an overall view of risk potential, actual risk and effects.
A further component of GESTIS is therefore the occupational disease documentation (BK-DOK), in which all cases of occupational disease reported since 1975 have been registered.
Essential to occupational disease documentation in the area of hazardous substances is the unambiguous, correct determination and recording of the relevant substances and products associated with each case. As a rule the determination is very time-consuming, but acquiring knowledge for prevention is impossible without the accurate identification of substances and products. Thus, for respiratory and skin diseases, which present a particular need for better understanding of possible causative agents, particular effort must be given to record substance and product use information as accurately as possible.
Literature data
The fourth component proposed for GESTIS was background information made available in the form of literature documents, so that the basic facts could be judged appropriately on the basis of current knowledge, and conclusions drawn. For this purpose an interface was developed with the literature database (ZIGUV-DOK), with a total of 50,000 references at present, of which 8,000 are on the subject of hazardous substances.
Linkage and Problem-oriented Preparation of Data
Information linkage
The components of GESTIS described above cannot stand in isolation if such a system is to be used efficiently. They require appropriate linkage possibilities, for example, between exposure data and cases of occupational disease. This linkage permits the creation of a truly integrated information system. The linkage occurs through core information that is available, coded in the standardized GESTIS coding system (see table 1).
Table 1. Standardized GESTIS code system
Object | Individual | Group |
Code | Code | |
Substance, product | ZVG central allocation number (BG) | SGS/PGS, substance/product group code (BG) |
Workplace | IBA sphere of activity of individual factory (BG) | AB sphere of activity (BIA) |
Exposed person | Activity (BIA, on the basis of the Federal Statistical Office’s systematic listing of occupations) |
Origins of codes appear in parentheses.
With the help of the GESTIS code both individual items of information can be linked to each other (e.g., measurement data from a particular workplace with a case of occupational disease that has occurred in the same or similar workplace) and statistically condensed, “typified” information (e.g., diseases related to particular work processes with average exposure data) can be obtained. With individual linkages of data (e.g., using the pension insurance number) the data protection laws must of course be strictly observed.
It is clear, therefore, that only a systematic coding system is capable of meeting these linkage requirements within the information system. Attention must, however, also be drawn to the possibility of linkage between various information systems and across national boundaries. These possibilities of linkage and comparison are crucially dependent on the use of internationally unified coding standards, if necessary in addition to national standards.
Preparation of problem-oriented and use-oriented information
The structure of GESTIS has at its centre the fact databases on substances and products, exposures, occupational diseases and literature, the data compiled both through specialists active at the centre and through the peripheral activities of the BG. For the application and use of the data, it is necessary to reach the users, centrally through publication in relevant journals (e.g., on the subject of the incidence of occupational disease), but also specifically through the advisory activities of the BG in their member firms.
For the most efficient possible use of information made available in GESTIS, the question arises regarding the problem-specific and target-group-specific preparation of facts as information. User-specific requirements are addressed in the fact databases on chemical substances and products—for example, in the depth of information or in the practice-oriented presentation of information. However, not all the specific requirements of possible users can be directly addressed in the fact databases. Target-group-specific and problem-specific preparation, if necessary supported by data processing, is required. Workplace-oriented information must be made available on the handling of hazardous substances. The most important data from the database must be extracted in a generally understandable and workplace-oriented form, for example, in the form of “workplace instructions”, which are prescribed in the occupational safety laws of many countries. Frequently too little attention is paid to this user-specific preparation of data as information for workers. Special information systems can prepare this information, but specialized information points which respond to individual queries also provide information and give the necessary support to firms. Within the framework of GESTIS this information- gathering and preparation proceeds, for instance, through branch-specific systems such as GISBAU (Hazardous Substances Information System of the Building Industry BG), GeSi (Hazardous Substances and Safety System), and through specialized information centres in the BG, in the BIA or in the association of the Berufsgenossenschaften.
GESTIS provides the relevant interfaces for data exchange and fosters cooperation by means of task-sharing:
Outlook
The emphasis of further development will be on prevention. In cooperation with the producers, plans encompass a comprehensive and up-to-date preparation of product data; the establishment of statistically determined workplace characteristic values derived from the exposure measurement data and from the substance-specific and product-specific documentation; and an evaluation in the occupational disease documentation.
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