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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.
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Another requirement is that the biomarker should be specific, at least under the circumstances of the study, for a particular type of exposure, with a clear-cut relationship to the degree of exposure. Otherwise, the result of the biomarker measurement may be too difficult to interpret. For proper interpretation of the measurement result of an exposure biomarker, the diagnostic validity must be known (i.e., the translation of the biomarker value into the magnitude of possible health risks). In this area, metals serve as a paradigm for biomarker research. Recent research has demonstrated the complexity and subtlety of dose-response relationships, with considerable difficulty in identifying no-effect levels and therefore also in defining tolerable exposures. However, this kind of research has also illustrated the types of investigation and the refinement that are necessary to uncover the relevant information. For most organic compounds, quantitative associations between exposures and the corresponding adverse health effects are not yet available; in many cases, even the primary target organs are not known for sure. In addition, evaluation of toxicity data and biomarker concentrations is often complicated by exposure to mixtures of substances, rather than exposure to a single compound at the time.
The critical effects can be of two types: those considered to have a threshold and those for which there may be some risk at any exposure level (non-threshold, genotoxic carcinogens and germ mutagens). Whenever possible, appropriate human data should be used as a basis for the risk assessment. In order to determine the threshold effects for the general population, assumptions concerning the exposure level (tolerable intake, biomarkers of exposure) have to be made such that the frequency of the critical effect in the population exposed to a given hazardous agent corresponds to the frequency of that effect in the general population. In lead exposure, the maximum recommended blood lead concentration for the general population (200 µg/l, median below 100 µg/l) (WHO 1987) is practically below the threshold value for the assumed critical effect-the elevated free erythrocyte protoporphyrin level, although it is not below the level associated with effects on the CNS in children or blood pressure in adults. In general, if data from well-conducted human population studies defining a no observed adverse effect level are the basis for safety evaluation, then the uncertainty factor of ten has been considered appropriate. In the case of occupational exposure the critical effects may refer to a certain part of the population (e.g. 10%). Accordingly, in occupational lead exposure the recommended health-based concentration of blood lead has been adopted to be 400 mg/l in men where a 10% response level for ALA-U of 5 mg/l occurred at PbB concentrations of about 300 to 400 mg/l. For the occupational exposure to cadmium (assuming the increased urinary excretion of low-weight proteins to be the critical effect), the level of 200 ppm cadmium in renal cortex has been regarded as the admissible value, for this effect has been observed in 10% of the exposed population. Both these values are under consideration for lowering, in many countries, at the present time (i.e.,1996).
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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.
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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.
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As with neurotoxicants, the existence of a threshold is usually assumed for reproductive toxicants. However, the actions of mutagenic compounds on germ cells may be considered an exception to this general assumption. For other endpoints, an RfD or RfC is calculated as with neurotoxicants by determination of the NOAEL or LOAEL and application of appropriate uncertainty factors. The effect used for determining the NOAEL or LOAEL is the most sensitive adverse reproductive endpoint from the most appropriate or most sensitive mammalian species (EPA 1994). Uncertainty factors include consideration of interspecies and intraspecies variation, ability to define a true NOAEL, and sensitivity of the endpoint detected.