" DISCLAIMER: The ILO does not take responsibility for content presented on this web portal that is presented in any language other than English, which is the language used for the initial production and peer-review of original content. Certain statistics have not been updated since the production of the 4th edition of the Encyclopaedia (1998)."

Sunday, 16 January 2011 19:15

Approaches to Hazard Identification: IARC

Written by
Rate this item
(0 votes)

The identification of carcinogenic risks to humans has been the objective of the IARC Monographs on the Evaluation of Carcinogenic Risks to Humans since 1971. To date, 69 volumes of monographs have been published or are in press, with evaluations of carcinogenicity of 836 agents or exposure circumstances (see Appendix).

These qualitative evaluations of carcinogenic risk to humans are equivalent to the hazard identification phase in the now generally accepted scheme of risk assessment, which involves identification of hazard, dose-response assessment (including extrapolation outside the limits of observations), exposure assessment and risk characterization.

The aim of the IARC Monographs programme has been to publish critical qualitative evaluations on the carcinogenicity to humans of agents (chemicals, groups of chemicals, complex mixtures, physical or biological factors) or exposure circumstances (occupational exposures, cultural habits) through international cooperation in the form of expert working groups. The working groups prepare monographs on a series of individual agents or exposures and each volume is published and widely distributed. Each monograph consists of a brief description of the physical and chemical properties of the agent; methods for its analysis; a description of how it is produced, how much is produced, and how it is used; data on occurrence and human exposure; summaries of case reports and epidemiological studies of cancer in humans; summaries of experimental carcinogenicity tests; a brief description of other relevant biological data, such as toxicity and genetic effects, that may indicate its possible mechanism of action; and an evaluation of its carcinogenicity. The first part of this general scheme is adjusted appropriately when dealing with agents other than chemicals or chemical mixtures.

The guiding principles for evaluating carcinogens have been drawn up by various ad-hoc groups of experts and are laid down in the Preamble to the Monographs (IARC 1994a).

Tools for Qualitative Carcinogenic Risk (Hazard) Identification

Associations are established by examining the available data from studies of exposed humans, the results of bioassays in experimental animals and studies of exposure, metabolism, toxicity and genetic effects in both humans and animals.

Studies of cancer in humans

Three types of epidemiological studies contribute to an assessment of carcinogenicity: cohort studies, case-control studies and correlation (or ecological) studies. Case reports of cancer may also be reviewed.

Cohort and case-control studies relate individual exposures under study to the occurrence of cancer in individuals and provide an estimate of relative risk (ratio of the incidence in those exposed to the incidence in those not exposed) as the main measure of association.

In correlation studies, the unit of investigation is usually whole populations (e.g., particular geographical areas) and cancer frequency is related to a summary measure of the exposure of the population to the agent. Because individual exposure is not documented, a causal relationship is less easy to infer from such studies than from cohort and case-control studies. Case reports generally arise from a suspicion, based on clinical experience, that the concurrence of two events—that is, a particular exposure and occurrence of a cancer—has happened rather more frequently than would be expected by chance. The uncertainties surrounding interpretation of case reports and correlation studies make them inadequate, except in rare cases, to form the sole basis for inferring a causal relationship.

In the interpretation of epidemiological studies, it is necessary to take into account the possible roles of bias and confounding. By bias is meant the operation of factors in study design or execution that lead erroneously to a stronger or weaker association than in fact exists between disease and an agent. By confounding is meant a situation in which the relationship with disease is made to appear stronger or weaker than it truly is as a result of an association between the apparent causal factor and another factor that is associated with either an increase or decrease in the incidence of the disease.

In the assessment of the epidemiological studies, a strong association (i.e., a large relative risk) is more likely to indicate causality than a weak association, although it is recognized that relative risks of small magnitude do not imply lack of causality and may be important if the disease is common. Associations that are replicated in several studies of the same design or using different epidemiological approaches or under different circumstances of exposure are more likely to represent a causal relationship than isolated observations from single studies. An increase in risk of cancer with increasing amounts of exposure is considered to be a strong indication of causality, although the absence of a graded response is not necessarily evidence against a causal relationship. Demonstration of a decline in risk after cessation of or reduction in exposure in individuals or in whole populations also supports a causal interpretation of the findings.

When several epidemiological studies show little or no indication of an association between an exposure and cancer, the judgement may be made that, in the aggregate, they show evidence suggesting lack of carcinogenicity. The possibility that bias, confounding or misclassification of exposure or outcome could explain the observed results must be considered and excluded with reasonable certainty. Evidence suggesting lack of carcinogenicity obtained from several epidemiological studies can apply only to those type(s) of cancer, dose levels and intervals between first exposure and observation of disease that were studied. For some human cancers, the period between first exposure and the development of clinical disease is seldom less than 20 years; latent periods substantially shorter than 30 years cannot provide evidence suggesting lack of carcinogenicity.

The evidence relevant to carcinogenicity from studies in humans is classified into one of the following categories:

Sufficient evidence of carcinogenicity. A causal relationship has been established between exposure to the agent, mixture or exposure circumstance and human cancer. That is, a positive relationship has been observed between the exposure and cancer in studies in which chance, bias and confounding could be ruled out with reasonable confidence.

Limited evidence of carcinogenicity. A positive association has been observed between exposure to the agent, mixture or exposure circumstance and cancer for which a causal interpretation is considered to be credible, but chance, bias or confounding cannot be ruled out with reasonable confidence.

Inadequate evidence of carcinogenicity. The available studies are of insufficient quality, consistency or statistical power to permit a conclusion regarding the presence or absence of a causal association, or no data on cancer in humans are available.

Evidence suggesting lack of carcinogenicity. There are several adequate studies covering the full range of levels of exposure that human beings are known to encounter, which are mutually consistent in not showing a positive association between exposure to the agent and the studied cancer at any observed level of exposure. A conclusion of “evidence suggesting lack of carcinogenicity” is inevitably limited to the cancer sites, conditions and levels of exposure and length of observation covered by the available studies.

The applicability of an evaluation of the carcinogenicity of a mixture, process, occupation or industry on the basis of evidence from epidemiological studies depends on time and place. The specific exposure, process or activity considered most likely to be responsible for any excess risk should be sought and the evaluation focused as narrowly as possible. The long latent period of human cancer complicates the interpretation of epidemiological studies. A further complication is the fact that humans are exposed simultaneously to a variety of chemicals, which can interact either to increase or decrease the risk for neoplasia.

Studies on carcinogenicity in experimental animals

Studies in which experimental animals (usually mice and rats) are exposed to potential carcinogens and examined for evidence of cancer were introduced about 50 years ago with the aim of introducing a scientific approach to the study of chemical carcinogenesis and to avoid some of the disadvantages of using only epidemiological data in humans. In the IARC Monographs all available, published studies of carcinogenicity in animals are summarized, and the degree of evidence of carcinogenicity is then classified into one of the following categories:

Sufficient evidence of carcinogenicity. A causal relationship has been established between the agent or mixture and an increased incidence of malignant neoplasms or of an appropriate combination of benign and malignant neoplasms in two or more species of animals or in two or more independent studies in one species carried out at different times or in different laboratories or under different protocols. Exceptionally, a single study in one species might be considered to provide sufficient evidence of carcinogenicity when malignant neoplasms occur to an unusual degree with regard to incidence, site, type of tumour or age at onset.

Limited evidence of carcinogenicity. The data suggest a carcinogenic effect but are limited for making a definitive evaluation because, for example, (a) the evidence of carcinogenicity is restricted to a single experiment; or (b) there are some unresolved questions regarding the adequacy of the design, conduct or interpretation of the study; or (c) the agent or mixture increases the incidence only of benign neoplasms or lesions of uncertain neoplastic potential, or of certain neoplasms which may occur spontaneously in high incidences in certain strains.

Inadequate evidence of carcinogenicity. The studies cannot be interpreted as showing either the presence or absence of a carcinogenic effect because of major qualitative or quantitative limitations, or no data on cancer in experimental animals are available.

Evidence suggesting lack of carcinogenicity. Adequate studies involving at least two species are available which show that, within the limits of the tests used, the agent or mixture is not carcinogenic. A conclusion of evidence suggesting lack of carcinogenicity is inevitably limited to the species, tumour sites and levels of exposure studied.

Other data relevant to an evaluationof carcinogenicity

Data on biological effects in humans that are of particular relevance include toxicological, kinetic and metabolic considerations and evidence of DNA binding, persistence of DNA lesions or genetic damage in exposed humans. Toxicological information, such as that on cytotoxicity and regeneration, receptor binding and hormonal and immunological effects, and data on kinetics and metabolism in experimental animals are summarized when considered relevant to the possible mechanism of the carcinogenic action of the agent. The results of tests for genetic and related effects are summarized for whole mammals including man, cultured mammalian cells and nonmammalian systems. Structure-activity relationships are mentioned when relevant.

For the agent, mixture or exposure circumstance being evaluated, the available data on end-points or other phenomena relevant to mechanisms of carcinogenesis from studies in humans, experimental animals and tissue and cell test systems are summarized within one or more of the following descriptive dimensions:

  •  evidence of genotoxicity (i.e., structural changes at the level of the gene): for example, structure-activity considerations, adduct formation, mutagenicity (effect on specific genes), chromosomal mutation or aneuploidy
  •  evidence of effects on the expression of relevant genes (i.e., functional changes at the intracellular level): for example, alterations to the structure or quantity of the product of a proto-oncogene or tumour suppressor gene, alterations to metabolic activation, inactivation or DNA repair
  •  evidence of relevant effects on cell behaviour (i.e., morphological or behavioural changes at the cellular or tissue level): for example, induction of mitogenesis, compensatory cell proliferation, preneoplasia and hyperplasia, survival of premalignant or malignant cells (immortalization, immunosuppression), effects on metastatic potential
  •  evidence from dose and time relationships of carcinogenic effects and interactions between agents: for example, early versus late stage, as inferred from epidemiological studies; initiation, promotion, progression or malignant conversion, as defined in animal carcinogenicity experiments; toxicokinetics.

 

These dimensions are not mutually exclusive, and an agent may fall within more than one. Thus, for example, the action of an agent on the expression of relevant genes could be summarized under both the first and second dimension, even if it were known with reasonable certainty that those effects resulted from genotoxicity.

Overall evaluations

Finally, the body of evidence is considered as a whole, in order to reach an overall evaluation of the carcinogenicity to humans of an agent, mixture or circumstance of exposure. An evaluation may be made for a group of chemicals when supporting data indicate that other, related compounds for which there is no direct evidence of capacity to induce cancer in humans or in animals may also be carcinogenic, a statement describing the rationale for this conclusion is added to the evaluation narrative.

The agent, mixture or exposure circumstance is described according to the wording of one of the following categories, and the designated group is given. The categorization of an agent, mixture or exposure circumstance is a matter of scientific judgement, reflecting the strength of the evidence derived from studies in humans and in experimental animals and from other relevant data.

Group 1

The agent (mixture) is carcinogenic to humans. The exposure circumstance entails exposures that are carcinogenic to humans.

This category is used when there is sufficient evidence of carcinogenicity in humans. Exceptionally, an agent (mixture) may be placed in this category when evidence in humans is less than sufficient but there is sufficient evidence of carcinogenicity in experimental animals and strong evidence in exposed humans that the agent (mixture) acts through a relevant mechanism of carcinogenicity.

Group 2

This category includes agents, mixtures and exposure circumstances for which, at one extreme, the degree of evidence of carcinogenicity in humans is almost sufficient, as well as those for which, at the other extreme, there are no human data but for which there is evidence of carcinogenicity in experimental animals. Agents, mixtures and exposure circumstances are assigned to either group 2A (probably carcinogenic to humans) or group 2B (possibly carcinogenic to humans) on the basis of epidemiological and experimental evidence of carcinogenicity and other relevant data.

Group 2A. The agent (mixture) is probably carcinogenic to humans. The exposure circumstance entails exposures that are probably carcinogenic to humans. This category is used when there is limited evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals. In some cases, an agent (mixture) may be classified in this category when there is inadequate evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals and strong evidence that the carcinogenesis is mediated by a mechanism that also operates in humans. Exceptionally, an agent, mixture or exposure circumstance may be classified in this category solely on the basis of limited evidence of carcinogenicity in humans.

Group 2B. The agent (mixture) is possibly carcinogenic to humans. The exposure circumstance entails exposures that are possibly carcinogenic to humans. This category is used for agents, mixtures and exposure circumstances for which there is limited evidence of carcinogenicity in humans and less than sufficient evidence of carcinogenicity in experimental animals. It may also be used when there is inadequate evidence of carcinogenicity in humans but there is sufficient evidence of carcinogenicity in experimental animals. In some instances, an agent, mixture or exposure circumstance for which there is inadequate evidence of carcinogenicity in humans but limited evidence of carcinogenicity in experimental animals together with supporting evidence from other relevant data may be placed in this group.

Group 3

The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals.

Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans.

Group 4

The agent (mixture) is probably not carcinogenic to humans. This category is used for agents or mixtures for which there is evidence suggesting lack of carcinogenicity in humans and in experimental animals. In some instances, agents or mixtures for which there is inadequate evidence of carcinogenicity in humans but evidence suggesting lack of carcinogenicity experimental animals, consistently and strongly supported by a broad range of other relevant data, may be classified in this group.

Classification systems made by humans are not sufficiently perfect to encompass all the complex entities of biology. They are, however, useful as guiding principles and may be modified as new knowledge of carcinogenesis becomes more firmly established. In the categorization of an agent, mixture or exposure circumstance, it is essential to rely on scientific judgements formulated by the group of experts.

Results to Date

To date, 69 volumes of IARC Monographs have been published or are in press, in which evaluations of carcinogenicity to humans have been made for 836 agents or exposure circumstances. Seventy-four agents or exposures have been evaluated as carcinogenic to humans (Group 1), 56 as probably carcinogenic to humans (Group 2A), 225 as possibly carcinogenic to humans (Group 2B) and one as probably not carcinogenic to humans (Group 4). For 480 agents or exposures, the available epidemiological and experimental data did not allow an evaluation of their carcinogenicity to humans (Group 3).

Importance of Mechanistic Data

The revised Preamble, which first appeared in volume 54 of the IARC Monographs, allows for the possibility that an agent for which epidemiological evidence of cancer is less than sufficient can be placed in Group 1 when there is sufficient evidence of carcinogenicity in experimental animals and strong evidence in exposed humans that the agent acts through a relevant mechanism of carcinogenicity. Conversely, an agent for which there is inadequate evidence of carcinogenicity in humans together with sufficient evidence in experimental animals and strong evidence that the mechanism of carcinogenesis does not operate in humans may be placed in Group 3 instead of the normally assigned Group 2B—possibly carcinogenic to humans—category.

The use of such data on mechanisms has been discussed on three recent occasions:

While it is generally accepted that solar radiation is carcinogenic to humans (Group 1), epidemiological studies on cancer in humans for UVA and UVB radiation from sun lamps provide only limited evidence of carcinogenicity. Special tandem base substitutions (GCTTT) have been observed in p53 tumour suppression genes in squamous-cell tumours at sun-exposed sites in humans. Although UVR can induce similar transitions in some experimental systems and UVB, UVA and UVC are carcinogenic in experimental animals, the available mechanistic data were not considered strong enough to allow the working group to classify UVB, UVA and UVC higher than Group 2A (IARC 1992). In a study published after the meeting (Kress et al. 1992), CCTTT transitions in p53 have been demonstrated in UVB-induced skin tumours in mice, which might suggest that UVB should also be classified as carcinogenic to humans (Group 1).

The second case in which the possibility of placing an agent in Group 1 in the absence of sufficient epidemiological evidence was considered was 4,4´-methylene-bis(2-chloroaniline) (MOCA). MOCA is carcinogenic in dogs and rodents and is comprehensively genotoxic. It binds to DNA through reaction with N-hydroxy MOCA and the same adducts that are formed in target tissues for carcinogenicity in animals have been found in urothelial cells from a small number of exposed humans. After lengthy discussions on the possibility of an upgrading, the working group finally made an overall evaluation of Group 2A, probably carcinogenic to humans (IARC 1993).

During a recent evaluation of ethylene oxide (IARC 1994b), the available epidemiological studies provided limited evidence of carcinogenicity in humans, and studies in experimental animals provided sufficient evidence of carcinogenicity. Taking into account the other relevant data that (1) ethylene oxide induces a sensitive, persistent, dose-related increase in the frequency of chromosomal aberrations and sister chromatid exchanges in peripheral lymphocytes and micronuclei in bone-marrow cells from exposed workers; (2) it has been associated with malignancies of the lymphatic and haematopoietic system in both humans and experimental animals; (3) it induces a dose-related increase in the frequency of haemoglobin adducts in exposed humans and dose-related increases in the numbers of adducts in both DNA and haemoglobin in exposed rodents; (4) it induces gene mutations and heritable translocations in germ cells of exposed rodents; and (5) it is a powerful mutagen and clastogen at all phylogenetic levels; ethylene oxide was classified as carcinogenic to humans (Group 1).

In the case where the Preamble allows for the possibility that an agent for which there is sufficient evidence of carcinogenicity in animals can be placed in Group 3 (instead of Group 2B, in which it would normally be categorized) when there is strong evidence that the mechanism of carcinogenicity in animals does not operate in humans, this possibility has not yet been used by any working group. Such a possibility could have been envisaged in the case of d-limonene had there been sufficient evidence of its carcinogenicity in animals, since there are data suggesting that α2-microglobulin production in male rat kidney is linked to the renal tumours observed.

Among the many chemicals nominated as priorities by an ad-hoc working group in December 1993, some common postulated intrinsic mechanisms of action appeared or certain classes of agents based upon their biological properties were identified. The working group recommended that before evaluations are made on such agents as peroxisome proliferators, fibres, dusts and thyrostatic agents within the Monographs programme, special ad-hoc groups should be convened to discuss the latest state of the art on their particular mechanisms of action.

 

Back

Read 3524 times Last modified on Thursday, 13 October 2011 20:50

Contents

Preface
Part I. The Body
Part II. Health Care
Part III. Management & Policy
Part IV. Tools and Approaches
Biological Monitoring
Epidemiology and Statistics
Ergonomics
Occupational Hygiene
Personal Protection
Record Systems and Surveillance
Toxicology
General Principles of Toxicology
Mechanisms of Toxicity
Toxicology Test Methods
Regulatory Toxicology
Resources
Part V. Psychosocial and Organizational Factors
Part VI. General Hazards
Part VII. The Environment
Part VIII. Accidents and Safety Management
Part IX. Chemicals
Part X. Industries Based on Biological Resources
Part XI. Industries Based on Natural Resources
Part XII. Chemical Industries
Part XIII. Manufacturing Industries
Part XIV. Textile and Apparel Industries
Part XV. Transport Industries
Part XVI. Construction
Part XVII. Services and Trade
Part XVIII. Guides

Toxicology Additional Resources

Click the Button below to view additional resources for this topic.

button

Toxicology References

Andersen, KE and HI Maibach. 1985. Contact allergy predictive tests on guinea pigs. Chap. 14 in Current Problems in Dermatology. Basel: Karger.

Ashby, J and RW Tennant. 1991. Definitive relationships among chemical structure, carcinogenicity and mutagenicity for 301 chemicals tested by the US NTP. Mutat Res 257:229-306.

Barlow, S and F Sullivan. 1982. Reproductive Hazards of Industrial Chemicals. London: Academic Press.

Barrett, JC. 1993a. Mechanisms of action of known human carcinogens. In Mechanisms of Carcinogenesis in Risk Identification, edited by H Vainio, PN Magee, DB McGregor, and AJ McMichael. Lyon: International Agency for Research on Cancer (IARC).

—. 1993b. Mechanisms of multistep carcinogenesis and carcinogen risk assessment. Environ Health Persp 100:9-20.

Bernstein, ME. 1984. Agents affecting the male reproductive system: Effects of structure on activity. Drug Metab Rev 15:941-996.

Beutler, E. 1992. The molecular biology of G6PD variants and other red cell defects. Annu Rev Med 43:47-59.

Bloom, AD. 1981. Guidelines for Reproductive Studies in Exposed Human Populations. White Plains, New York: March of Dimes Foundation.

Borghoff, S, B Short and J Swenberg. 1990. Biochemical mechanisms and pathobiology of a-2-globulin nephropathy. Annu Rev Pharmacol Toxicol 30:349.

Burchell, B, DW Nebert, DR Nelson, KW Bock, T Iyanagi, PLM Jansen, D Lancet, GJ Mulder, JR Chowdhury, G Siest, TR Tephly, and PI Mackenzie. 1991. The UPD-glucuronosyltransferase gene superfamily: Suggested nomenclature based on evolutionary divergence. DNA Cell Biol 10:487-494.

Burleson, G, A Munson, and J Dean. 1995. Modern Methods in Immunotoxicology. New York: Wiley.

Capecchi, M. 1994. Targeted gene replacement. Sci Am 270:52-59.

Carney, EW. 1994. An integrated perspective on the developmental toxicity of ethylene glycol. Rep Toxicol 8:99-113.

Dean, JH, MI Luster, AE Munson, and I Kimber. 1994. Immunotoxicology and Immunopharmacology. New York: Raven Press.

Descotes, J. 1986. Immunotoxicology of Drugs and Chemicals. Amsterdam: Elsevier.

Devary, Y, C Rosette, JA DiDonato, and M Karin. 1993. NFkB activation by ultraviolet light not dependent on a nuclear signal. Science 261:1442-1445.

Dixon, RL. 1985. Reproductive Toxicology. New York: Raven Press.

Duffus, JH. 1993. Glossary for chemists of terms used in toxicology. Pure Appl Chem 65:2003-2122.

Elsenhans, B, K Schuemann, and W Forth. 1991. Toxic metals: Interactions with essential metals. In Nutrition, Toxicity and Cancer, edited by IR Rowland. Boca-Raton: CRC Press.

Environmental Protection Agency (EPA). 1992. Guidelines for exposure assessment. Federal Reg 57:22888-22938.

—. 1993. Principles of neurotoxicity risk assessment. Federal Reg 58:41556-41598.

—. 1994. Guidelines for Reproductive Toxicity Assessment. Washington, DC: US EPA: Office of Research and Development.

Fergusson, JE. 1990. The Heavy Elements. Chap. 15 in Chemistry, Environmental Impact and Health Effects. Oxford: Pergamon.

Gehring, PJ, PG Watanabe, and GE Blau. 1976. Pharmacokinetic studies in evaluation of the toxicological and environmental hazard of chemicals. New Concepts Saf Eval 1(Part 1, Chapter 8):195-270.

Goldstein, JA and SMF de Morais. 1994. Biochemistry and molecular biology of the human CYP2C subfamily. Pharmacogenetics 4:285-299.

Gonzalez, FJ. 1992. Human cytochromes P450: Problems and prospects. Trends Pharmacol Sci 13:346-352.

Gonzalez, FJ, CL Crespi, and HV Gelboin. 1991. cDNA-expressed human cytochrome P450: A new age in molecular toxicology and human risk assessment. Mutat Res 247:113-127.

Gonzalez, FJ and DW Nebert. 1990. Evolution of the P450 gene superfamily: Animal-plant “warfare,” molecular drive, and human genetic differences in drug oxidation. Trends Genet 6:182-186.

Grant, DM. 1993. Molecular genetics of the N-acetyltransferases. Pharmacogenetics 3:45-50.

Gray, LE, J Ostby, R Sigmon, J Ferrel, R Linder, R Cooper, J Goldman, and J Laskey. 1988. The development of a protocol to assess reproductive effects of toxicants in the rat. Rep Toxicol 2:281-287.

Guengerich, FP. 1989. Polymorphism of cytochrome P450 in humans. Trends Pharmacol Sci 10:107-109.

—. 1993. Cytochrome P450 enzymes. Am Sci 81:440-447.

Hansch, C and A Leo. 1979. Substituent Constants for Correlation Analysis in Chemistry and Biology. New York: Wiley.

Hansch, C and L Zhang. 1993. Quantitative structure-activity relationships of cytochrome P450. Drug Metab Rev 25:1-48.

Hayes AW. 1988. Principles and Methods of Toxicology. 2nd ed. New York: Raven Press.

Heindell, JJ and RE Chapin. 1993. Methods in Toxicology: Male and Female Reproductive Toxicology. Vol. 1 and 2. San Diego, Calif.: Academic Press.

International Agency for Research on Cancer (IARC). 1992. Solar and ultraviolet radiation. Lyon: IARC.

—. 1993. Occupational Exposures of Hairdressers and Barbers and Personal Use of Hair Colourants: Some Hair Dyes, Cosmetic Colourants, Industrial Dyestuffs and Aromatic Amines. Lyon: IARC.

—. 1994a. Preamble. Lyon: IARC.

—. 1994b. Some Industrial Chemicals. Lyon: IARC.

International Commission on Radiological Protection (ICRP). 1965. Principles of Environmental Monitoring Related to the Handling of Radioactive Materials. Report of Committee IV of The International Commission On Radiological Protection. Oxford: Pergamon.

International Program on Chemical Safety (IPCS). 1991. Principles and Methods for the Assessment of Nephrotoxicity Associated With Exposure to Chemicals, EHC 119. Geneva: WHO.

—. 1996. Principles and Methods for Assessing Direct Immunotoxicity Associated With Exposure to Chemicals, EHC 180. Geneva: WHO.

Johanson, G and PH Naslund. 1988. Spreadsheet programming - a new approach in physiologically based modeling of solvent toxicokinetics. Toxicol Letters 41:115-127.

Johnson, BL. 1978. Prevention of Neurotoxic Illness in Working Populations. New York: Wiley.

Jones, JC, JM Ward, U Mohr, and RD Hunt. 1990. Hemopoietic System, ILSI Monograph, Berlin: Springer Verlag.

Kalow, W. 1962. Pharmocogenetics: Heredity and the Response to Drugs. Philadelphia: WB Saunders.

—. 1992. Pharmocogenetics of Drug Metabolism. New York: Pergamon.

Kammüller, ME, N Bloksma, and W Seinen. 1989. Autoimmunity and Toxicology. Immune Dysregulation Induced By Drugs and Chemicals. Amsterdam: Elsevier Sciences.

Kawajiri, K, J Watanabe, and SI Hayashi. 1994. Genetic polymorphism of P450 and human cancer. In Cytochrome P450: Biochemistry, Biophysics and Molecular Biology, edited by MC Lechner. Paris: John Libbey Eurotext.

Kehrer, JP. 1993. Free radicals as mediators of tissue injury and disease. Crit Rev Toxicol 23:21-48.

Kellerman, G, CR Shaw, and M Luyten-Kellerman. 1973. Aryl hydrocarbon hydroxylase inducibility and bronochogenic carcinoma. New Engl J Med 289:934-937.

Khera, KS. 1991. Chemically induced alterations maternal homeostasis and histology of conceptus: Their etiologic significance in rat fetal anomalies. Teratology 44:259-297.

Kimmel, CA, GL Kimmel, and V Frankos. 1986. Interagency Regulatory Liaison Group workshop on reproductive toxicity risk assessment. Environ Health Persp 66:193-221.

Klaassen, CD, MO Amdur and J Doull (eds.). 1991. Casarett and Doull´s Toxicology. New York: Pergamon Press.

Kramer, HJ, EJHM Jansen, MJ Zeilmaker, HJ van Kranen and ED Kroese. 1995. Quantitative methods in toxicology for human dose-response assessment. RIVM-report nr. 659101004.

Kress, S, C Sutter, PT Strickland, H Mukhtar, J Schweizer, and M Schwarz. 1992. Carcinogen-specific mutational pattern in the p53 gene in ultraviolet B radiation-induced squamous cell carcinomas of mouse skin. Cancer Res 52:6400-6403.

Krewski, D, D Gaylor, M Szyazkowicz. 1991. A model-free approach to low-dose extrapolation. Env H Pers 90:270-285.

Lawton, MP, T Cresteil, AA Elfarra, E Hodgson, J Ozols, RM Philpot, AE Rettie, DE Williams, JR Cashman, CT Dolphin, RN Hines, T Kimura, IR Phillips, LL Poulsen, EA Shephare, and DM Ziegler. 1994. A nomenclature for the mammalian flavin-containing monooxygenase gene family based on amino acid sequence identities. Arch Biochem Biophys 308:254-257.

Lewalter, J and U Korallus. 1985. Blood protein conjugates and acetylation of aromatic amines. New findings on biological monitoring. Int Arch Occup Environ Health 56:179-196.

Majno, G and I Joris. 1995. Apoptosis, oncosis, and necrosis: An overview of cell death. Am J Pathol 146:3-15.

Mattison, DR and PJ Thomford. 1989. The mechanism of action of reproductive toxicants. Toxicol Pathol 17:364-376.

Meyer, UA. 1994. Polymorphisms of cytochrome P450 CYP2D6 as a risk factor in carcinogenesis. In Cytochrome P450: Biochemistry, Biophysics and Molecular Biology, edited by MC Lechner. Paris: John Libbey Eurotext.

Moller, H, H Vainio and E Heseltine. 1994. Quantitative estimation and prediction of risk at the International Agency for Research on Cancer. Cancer Res 54:3625-3627.

Moolenaar, RJ. 1994. Default assumptions in carcinogen risk assessment used by regulatory agencies. Regul Toxicol Pharmacol 20:135-141.

Moser, VC. 1990. Screening approaches to neurotoxicity: A functional observational battery. J Am Coll Toxicol 1:85-93.

National Research Council (NRC). 1983. Risk Assessment in the Federal Government: Managing the Process. Washington, DC: NAS Press.

—. 1989. Biological Markers in Reproductive Toxicity. Washington, DC: NAS Press.

—. 1992. Biologic Markers in Immunotoxicology. Subcommittee on Toxicology. Washington, DC: NAS Press.

Nebert, DW. 1988. Genes encoding drug-metabolizing enzymes: Possible role in human disease. In Phenotypic Variation in Populations, edited by AD Woodhead, MA Bender, and RC Leonard. New York: Plenum Publishing.

—. 1994. Drug-metabolizing enzymes in ligand-modulated transcription. Biochem Pharmacol 47:25-37.

Nebert, DW and WW Weber. 1990. Pharmacogenetics. In Principles of Drug Action. The Basis of Pharmacology, edited by WB Pratt and PW Taylor. New York: Churchill-Livingstone.

Nebert, DW and DR Nelson. 1991. P450 gene nomenclature based on evolution. In Methods of Enzymology. Cytochrome P450, edited by MR Waterman and EF Johnson. Orlando, Fla: Academic Press.

Nebert, DW and RA McKinnon. 1994. Cytochrome P450: Evolution and functional diversity. Prog Liv Dis 12:63-97.

Nebert, DW, M Adesnik, MJ Coon, RW Estabrook, FJ Gonzalez, FP Guengerich, IC Gunsalus, EF Johnson, B Kemper, W Levin, IR Phillips, R Sato, and MR Waterman. 1987. The P450 gene superfamily: Recommended nomenclature. DNA Cell Biol 6:1-11.

Nebert, DW, DR Nelson, MJ Coon, RW Estabrook, R Feyereisen, Y Fujii-Kuriyama, FJ Gonzalez, FP Guengerich, IC Gunsalas, EF Johnson, JC Loper, R Sato, MR Waterman, and DJ Waxman. 1991. The P450 superfamily: Update on new sequences, gene mapping, and recommended nomenclature. DNA Cell Biol 10:1-14.

Nebert, DW, DD Petersen, and A Puga. 1991. Human AH locus polymorphism and cancer: Inducibility of CYP1A1 and other genes by combustion products and dioxin. Pharmacogenetics 1:68-78.

Nebert, DW, A Puga, and V Vasiliou. 1993. Role of the Ah receptor and the dioxin-inducible [Ah] gene battery in toxicity, cancer, and signal transduction. Ann NY Acad Sci 685:624-640.

Nelson, DR, T Kamataki, DJ Waxman, FP Guengerich, RW Estabrook, R Feyereisen, FJ Gonzalez, MJ Coon, IC Gunsalus, O Gotoh, DW Nebert, and K Okuda. 1993. The P450 superfamily: Update on new sequences, gene mapping, accession numbers, early trivial names of enzymes, and nomenclature. DNA Cell Biol 12:1-51.

Nicholson, DW, A All, NA Thornberry, JP Vaillancourt, CK Ding, M Gallant, Y Gareau, PR Griffin, M Labelle, YA Lazebnik, NA Munday, SM Raju, ME Smulson, TT Yamin, VL Yu, and DK Miller. 1995. Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature 376:37-43.

Nolan, RJ, WT Stott, and PG Watanabe. 1995. Toxicologic data in chemical safety evaluation. Chap. 2 in Patty’s Industrial Hygiene and Toxicology, edited by LJ Cralley, LV Cralley, and JS Bus. New York: John Wiley & Sons.

Nordberg, GF. 1976. Effect and Dose-Response Relationships of Toxic Metals. Amsterdam: Elsevier.

Office of Technology Assessment (OTA). 1985. Reproductive Hazards in the Workplace. Document No. OTA-BA-266. Washington, DC: Government Printing Office.

—. 1990. Neurotoxicity: Identifying and Controlling Poisons of the Nervous System. Document No. OTA-BA-436. Washington, DC: Government Printing Office.

Organization for Economic Cooperation and Development (OECD). 1993. US EPA/EC Joint Project On the Evaluation of (Quantitative) Structure Activity Relationships. Paris: OECD.

Park, CN and NC Hawkins. 1993. Technology review; an overview of cancer risk assessment. Toxicol Methods 3:63-86.

Pease, W, J Vandenberg, and WK Hooper. 1991. Comparing alternative approaches to establishing regulatory levels for reproductive toxicants: DBCP as a case study. Environ Health Persp 91:141-155.

Prpi<F"WP MultinationalA Roman"P6.5>ƒ<F255P255>-Maji<F"WP MultinationalA Roman"P6.5%0>ƒ<F255P255>, D, S Telišman, and S Kezi<F"WP MultinationalA Roman"P6.5%0>ƒ<F255P255>. 1984. In vitro study on lead and alcohol interaction and the inhibition of erythrocyte delta-aminolevulinic acid dehydratase in man. Scand J Work Environ Health 10:235-238.

Reitz, RH, RJ Nolan, and AM Schumann. 1987. Development of multispecies, multiroute pharmacokinetic models for methylene chloride and 1,1,1-trichloroethane. In Pharmacokinetics and Risk Assessment, Drinking Water and Health. Washington, DC: National Academy Press.

Roitt, I, J Brostoff, and D Male. 1989. Immunology. London: Gower Medical Publishing.

Sato, A. 1991. The effect of environmental factors on the pharmacokinetic behaviour of organic solvent vapours. Ann Occup Hyg 35:525-541.

Silbergeld, EK. 1990. Developing formal risk assessment methods for neurotoxicants: An evaluation of the state of the art. In Advances in Neurobehavioral Toxicology, edited by BL Johnson, WK Anger, A Durao, and C Xintaras. Chelsea, Mich.: Lewis.

Spencer, PS and HH Schaumberg. 1980. Experimental and Clinical Neurotoxicology. Baltimore: Williams & Wilkins.

Sweeney, AM, MR Meyer, JH Aarons, JL Mills, and RE LePorte. 1988. Evaluation of methods for the prospective identification of early fetal losses in environmental epidemiology studies. Am J Epidemiol 127:843-850.

Taylor, BA, HJ Heiniger, and H Meier. 1973. Genetic analysis of resistance to cadmium-induced testicular damage in mice. Proc Soc Exp Biol Med 143:629-633.

Telišman, S. 1995. Interactions of essential and/or toxic metals and metalloids regarding interindividual differences in susceptibility to various toxicants and chronic diseases in man. Arh rig rada toksikol 46:459-476.

Telišman, S, A Pinent, and D Prpi<F"WP MultinationalA Roman"P6.5J255%0>ƒ<F255P255J0>-Maji<F"WP MultinationalA Roman"P6.5J255%0>ƒ<F255P255J0>. 1993. Lead interference in zinc metabolism and the lead and zinc interaction in humans as a possible explanation of apparent individual susceptibility to lead. In Heavy Metals in the Environment, edited by RJ Allan and JO Nriagu. Edinburgh: CEP Consultants.

Telišman, S, D Prpi<F"WP MultinationalA Roman"P6.5%0>ƒ<F255P255>-Maji<F"WP MultinationalA Roman"P6.5%0>ƒ<F255P255>, and S Kezi<F"WP MultinationalA Roman"P6.5%0>ƒ<F255P255>. 1984. In vivo study on lead and alcohol interaction and the inhibition of erythrocyte delta-aminolevulinic acid dehydratase in man. Scand J Work Environ Health 10:239-244.

Tilson, HA and PA Cabe. 1978. Strategies for the assessment of neurobehavioral consequences of environmental factors. Environ Health Persp 26:287-299.

Trump, BF and AU Arstila. 1971. Cell injury and cell death. In Principles of Pathobiology, edited by MF LaVia and RB Hill Jr. New York: Oxford Univ. Press.

Trump, BF and IK Berezesky. 1992. The role of cytosolic Ca2<F"Symbol"P8>+<F255P255> in cell injury, necrosis and apoptosis. Curr Opin Cell Biol 4:227-232.

—. 1995. Calcium-mediated cell injury and cell death. FASEB J 9:219-228.

Trump, BF, IK Berezesky, and A Osornio-Vargas. 1981. Cell death and the disease process. The role of cell calcium. In Cell Death in Biology and Pathology, edited by ID Bowen and RA Lockshin. London: Chapman & Hall.

Vos, JG, M Younes and E Smith. 1995. Allergic Hyper-sensitivities Induced by Chemicals: Recommendations for Prevention Published on Behalf of the World Health Organization Regional Office for Europe. Boca Raton, FL: CRC Press.

Weber, WW. 1987. The Acetylator Genes and Drug Response. New York: Oxford Univ. Press.

World Health Organization (WHO). 1980. Recommended Health-Based Limits in Occupational Exposure to Heavy Metals. Technical Report Series, No. 647. Geneva: WHO.

—. 1986. Principles and Methods for the Assessment of Neurotoxicity Associated With Exposure to Chemicals. Environmental Health Criteria, No.60. Geneva: WHO.

—. 1987. Air Quality Guidelines for Europe. European Series, No. 23. Copenhagen: WHO Regional Publications.

—. 1989. Glossary of Terms On Chemical Safety for Use in IPCS Publications. Geneva: WHO.

—. 1993. The Derivation of Guidance Values for Health-Based Exposure Limits. Environmental Health Criteria, unedited draft. Geneva: WHO.

Wyllie, AH, JFR Kerr, and AR Currie. 1980. Cell death: The significance of apoptosis. Int Rev Cytol 68:251-306.

@REFS LABEL = Other relevant readings

Albert, RE. 1994. Carcinogen risk assessment in the US Environmental Protection Agency. Crit. Rev. Toxicol 24:75-85.

Alberts, B, D Bray, J Lewis, M Raff, K Roberts, and JD Watson. 1988. Molecular Biology of the Cell. New York: Garland Publishing.

Ariens, EJ. 1964. Molecular Pharmacology. Vol.1. New York: Academic Press.

Ariens, EJ, E Mutschler, and AM Simonis. 1978. Allgemeine Toxicologie [General Toxicology]. Stuttgart: Georg Thieme Verlag.

Ashby, J and RW Tennant. 1994. Prediction of rodent carcinogenicity for 44 chemicals: Results. Mutagenesis 9:7-15.

Ashford, NA, CJ Spadafor, DB Hattis, and CC Caldart. 1990. Monitoring the Worker for Exposure and Disease. Baltimore: Johns Hopkins Univ. Press.

Balabuha, NS and GE Fradkin. 1958. Nakoplenie radioaktivnih elementov v organizme I ih vivedenie [Accumulation of Radioactive Elements in the Organism and their Excretion]. Moskva: Medgiz.

Balls, M, J Bridges, and J Southee. 1991. Animals and Alternatives in Toxicology Present Status and Future Prospects. Nottingham, UK: The Fund for Replacement of Animals in Medical Experiments.

Berlin, A, J Dean, MH Draper, EMB Smith, and F Spreafico. 1987. Immunotoxicology. Dordrecht: Martinus Nijhoff.

Boyhous, A. 1974. Breathing. New York: Grune & Stratton.

Brandau, R and BH Lippold. 1982. Dermal and Transdermal Absorption. Stuttgart: Wissenschaftliche Verlagsgesellschaft.

Brusick, DJ. 1994. Methods for Genetic Risk Assessment. Boca Raton: Lewis Publishers.

Burrell, R. 1993. Human immune toxicity. Mol Aspects Med 14:1-81.

Castell, JV and MJ Gómez-Lechón. 1992. In Vitro Alternatives to Animal Pharmaco-Toxicology. Madrid, Spain: Farmaindustria.

Chapman, G. 1967. Body Fluids and their Functions. London: Edward Arnold.

Committee on Biological Markers of the National Research Council. 1987. Biological markers in environmental health research. Environ Health Persp 74:3-9.

Cralley, LJ, LV Cralley and JS Bus (eds.). 1978. Patty’s Industrial Hygiene and Toxicology. New York: Witey.

Dayan, AD, RF Hertel, E Heseltine, G Kazantis, EM Smith, and MT Van der Venne. 1990. Immunotoxicity of Metals and Immunotoxicology. New York: Plenum Press.

Djuric, D. 1987. Molecular-cellular Aspects of Occupational Exposure to Toxic Chemicals. In Part 1 Toxicokinetics. Geneva: WHO.

Duffus, JH. 1980. Environmental Toxicology. London: Edward Arnold.

ECOTOC. 1986. Structure-Activity Relationship in Toxicology and Ecotoxicology, Monograph No. 8. Brussels: ECOTOC.

Forth, W, D Henschler, and W Rummel. 1983. Pharmakologie und Toxikologie. Mannheim: Biblio- graphische Institut.

Frazier, JM. 1990. Scientific criteria for Validation of in VitroToxicity Tests. OECD Environmental Monograph, no. 36. Paris: OECD.

—. 1992. In Vitro Toxicity—Applications to Safety Evaluation. New York: Marcel Dekker.

Gad, SC. 1994. In Vitro Toxicology. New York: Raven Press.

Gadaskina, ID. 1970. Zhiroraya tkan I yadi [Fatty Tissues and Toxicants]. In Aktualnie Vaprosi promishlenoi toksikolgii [Actual Problems in Occupational Toxicology], edited by NV Lazarev. Leningrad: Ministry of Health RSFSR.

Gaylor, DW. 1983. The use of safety factors for controlling risk. J Toxicol Environ Health 11:329-336.

Gibson, GG, R Hubbard, and DV Parke. 1983. Immunotoxicology. London: Academic Press.

Goldberg, AM. 1983-1995. Alternatives in Toxicology. Vol. 1-12. New York: Mary Ann Liebert.

Grandjean, P. 1992. Individual susceptibility to toxicity. Toxicol Letters 64/65:43-51.

Hanke, J and JK Piotrowski. 1984. Biochemyczne podstawy toksikologii [Biochemical Basis of Toxicology]. Warsaw: PZWL.

Hatch, T and P Gross. 1954. Pulmonary Deposition and Retention of Inhaled Aerosols. New York: Academic Press.

Health Council of the Netherlands: Committee on the Evaluation of the Carcinogenicity of Chemical Substances. 1994. Risk assessment of carcinogenic chemicals in The Netherlands. Regul Toxicol Pharmacol 19:14-30.

Holland, WC, RL Klein, and AH Briggs. 1967. Molekulaere Pharmakologie.

Huff, JE. 1993. Chemicals and cancer in humans: First evidence in experimental animals. Environ Health Persp 100:201-210.

Klaassen, CD and DL Eaton. 1991. Principles of toxicology. Chap. 2 in Casarett and Doull’s Toxicology, edited by CD Klaassen, MO Amdur and J Doull. New York: Pergamon Press.

Kossover, EM. 1962. Molecular Biochemistry. New York: McGraw-Hill.

Kundiev, YI. 1975.Vssavanie pesticidov cherez kozsu I profilaktika otravlenii [Absorption of Pesticides Through Skin and Prevention of Intoxication]. Kiev: Zdorovia.

Kustov, VV, LA Tiunov, and JA Vasiljev. 1975. Komvinovanie deistvie promishlenih yadov [Combined Effects of Industrial Toxicants]. Moskva: Medicina.

Lauwerys, R. 1982. Toxicologie industrielle et intoxications professionelles. Paris: Masson.

Li, AP and RH Heflich. 1991. Genetic Toxicology. Boca Raton: CRC Press.

Loewey, AG and P Siekewitz. 1969. Cell Structure and Functions. New York: Holt, Reinhart and Winston.

Loomis, TA. 1976. Essentials of Toxicology. Philadelphia: Lea & Febiger.

Mendelsohn, ML and RJ Albertini. 1990. Mutation and the Environment, Parts A-E. New York: Wiley Liss.

Mettzler, DE. 1977. Biochemistry. New York: Academic Press.

Miller, K, JL Turk, and S Nicklin. 1992. Principles and Practice of Immunotoxicology. Oxford: Blackwells Scientific.

Ministry of International Trade and Industry. 1981. Handbook of Existing Chemical Substances. Tokyo: Chemical Daily Press.

—. 1987. Application for Approval of Chemicals by Chemical Substances Control Law. (In Japanese and in English). Tokyo: Kagaku Kogyo Nippo Press.

Montagna, W. 1956. The Structure and Function of Skin. New York: Academic Press.

Moolenaar, RJ. 1994. Carcinogen risk assessment: international comparison. Regul Toxicol Pharmacol 20:302-336.

National Research Council. 1989. Biological Markers in Reproductive Toxicity. Washington, DC: NAS Press.

Neuman, WG and M Neuman. 1958. The Chemical Dynamic of Bone Minerals. Chicago: The Univ. of Chicago Press.

Newcombe, DS, NR Rose, and JC Bloom. 1992. Clinical Immunotoxicology. New York: Raven Press.

Pacheco, H. 1973. La pharmacologie moleculaire. Paris: Presse Universitaire.

Piotrowski, JK. 1971. The Application of Metabolic and Excretory Kinetics to Problems of Industrial Toxicology. Washington, DC: US Department of Health, Education and Welfare.

—. 1983. Biochemical interactions of heavy metals: Methalothionein. In Health Effects of Combined Exposure to Chemicals. Copenhagen: WHO Regional Office for Europe.

Proceedings of the Arnold O. Beckman/IFCC Conference of Environmental Toxicology Biomarkers of Chemical Exposure. 1994. Clin Chem 40(7B).

Russell, WMS and RL Burch. 1959. The Principles of Humane Experimental Technique. London: Methuen & Co. Reprinted by Universities Federation for Animal Welfare,1993.

Rycroft, RJG, T Menné, PJ Frosch, and C Benezra. 1992. Textbook of Contact Dermatitis. Berlin: Springer-Verlag.

Schubert, J. 1951. Estimating radioelements in exposed individuals. Nucleonics 8:13-28.

Shelby, MD and E Zeiger. 1990. Activity of human carcinogens in the Salmonella and rodent bone-marrow cytogenetics tests. Mutat Res 234:257-261.

Stone, R. 1995. A molecular approach to cancer risk. Science 268:356-357.

Teisinger, J. 1984. Expositiontest in der Industrietoxikologie [Exposure Tests in Industrial Toxicology]. Berlin: VEB Verlag Volk und Gesundheit.

US Congress. 1990. Genetic Monitoring and Screening in the Workplace, OTA-BA-455. Washington, DC: US Government Printing Office.

VEB. 1981. Kleine Enzyklopaedie: Leben [Life]. Leipzig: VEB Bibliographische Institut.

Weil, E. 1975. Elements de toxicologie industrielle [Elements of Industrial Toxicology]. Paris: Masson et Cie.

World Health Organization (WHO). 1975. Methods Used in USSR for Establishing Safe Levels of Toxic Substances. Geneva: WHO.

1978. Principles and Methods for Evaluating the Toxicity of Chemicals, Part 1. Environmental Health Criteria, no.6. Geneva: WHO.

—. 1981. Combined Exposure to Chemicals, Interim Document no.11. Copenhagen: WHO Regional Office for Europe.

—. 1986. Principles of Toxicokinetic Studies. Environmental Health Criteria, no. 57. Geneva: WHO.

Yoftrey, JM and FC Courtice. 1956. Limphatics, Lymph and Lymphoid Tissue. Cambridge: Harvard Univ. Press.

Zakutinskiy, DI. 1959. Voprosi toksikologii radioaktivnih veshchestv [Problems of Toxicology of Radioactive Materials]. Moscow: Medgiz.

Zurlo, J, D Rudacille, and AM Goldberg. 1993. Animals and Alternatives in Testing: History, Science and Ethics. New York: Mary Ann Liebert.