Human Health Risk Assessment for Priority Substances

2.0 Database for Assessment of " Toxic" under paragraph 11(c) of CEPA

Initially in the determination of whether a substance is "toxic" under paragraph 11(c) of CEPA, information on levels in the general (non-occupational) environment to which the population of Canada is exposed, and on the intrinsic toxicological properties of the substance, is collected and critically evaluated.

2.1 Exposure

To the extent possible, information on concentrations of Priority Substances acquired in national surveys of ambient air, drinking water, soil, foodstuffs and consumer products within Canada is used as the basis for the assessment of exposure of the general (non-occupationally exposed) population. Concentrations in various tissues or biological fluids (e.g., adipose tissue or breast milk) of the general population are also used as a basis for estimation of human exposure. In those cases where relevant Canadian data are lacking or inadequate, information on the levels of Priority Substances in various environmental media, foods, consumer products, or biological tissues and fluids in the general population from other countries (primarily the United States) is used as a basis for assessment of the exposure of the general population of Canada. In addition to size (i.e., number of samples and locations) and representativeness (i.e., range of locations sampled) of available surveys, the sensitivity, precision and accuracy of the analytical methodology employed is also considered in the selection of data as a basis for estimation of exposure. In general, mean concentrations in various environmental media used in estimating exposure are those reported by the authors of relevant accounts, although, wherever possible, the values which have been assigned to non-detectable concentrations in the calculation of means are indicated. Where it is necessary to calculate mean concentrations from raw data, the concentration in samples in which the compound has not been detected is considered to be the limit of detection, though it is recognized that this will lead to an overestimate of exposure. Where appropriate, information on concentrations of Priority Substances in specific locales is also used as a basis for estimation of exposure of some "high exposure subgroups" in the general population.

In some cases where data on concentrations of Priority Substances in environmental media within Canada or elsewhere are not available or are inadequate, where appropriate, population exposure is estimated based on levels in air, water, soil and food (fish) predicted by modelling of information on use patterns and physical/chemical properties (e.g., fugacity modelling). However, owing to the considerable uncertainty in values predicted by these models, they are only relied upon in the determination of "toxic" in cases where estimated total daily intake is markedly less (i.e., by many orders of magnitude) than intakes, considered on the basis of available data, to which it is believed that a person can be exposed over a lifetime without deleterious effect. In cases where total daily intake estimated on the basis of concentrations in the environment predicted by modelling are only somewhat less than or exceed that to which it is believed that a person can be exposed over a lifetime without deleterious effect, acquisition of monitoring data on actual concentrations in the environment may be required, prior to reaching a conclusion that the substance is "toxic".

Information on the duration and frequency of exposure is also important in assessing the total daily intake of Priority Substances by the general population under CEPA. Relevant data on behaviour and activity patterns are also considered, therefore, in the development of estimates of exposure of the general population.

2.2 Effects

Effects of exposure to existing substances are generally classified in the following broad categories: organ-specific, neurological/behavioural, reproductive/developmental, immunological, carcinogenic and mutagenic. These effects are manifested at the biochemical, cellular, histopathological and morphological levels. Such effects vary depending upon the dosage, route of exposure (e.g., ingestion, inhalation or dermal absorption), frequency and/or duration of exposure, species (and strain in the case of animals), physiological state, sex and age of the exposed population. Toxicological effects resulting from exposure to chemical substances may be brief or prolonged, reversible or irreversible, immediate or delayed. The nature, number, severity, incidence and/or prevalence of specific toxicological effects in populations (of either humans or animal species) exposed to chemical substances generally increase with increasing dose or level of exposure; this is commonly referred to as the exposure- or dose-response relationship.

For most existing substances, data on the toxicological effects resulting from exposure are restricted to information obtained from studies involving laboratory animals. Occasionally, information derived from studies of human populations (principally epidemiological investigations) forms an integral part of the database upon which the assessment of "toxic" under paragraph 11(c) of CEPA is based. Clearly, data on effects in humans are preferred as a basis of assessment of "toxic" under CEPA since such information obviates the need to extrapolate across species; however, in most cases, such data are limited or inadequate.

Often, there are case reports on the health of exposed individuals included in the literature; however, they are not weighted heavily in assessments for Priority Substances, owing to the nature of and general lack of quantitation of exposure (generally short-term exposure to concentrations much greater than those in the general environment) and lack of statistical reliability. In some cases, information from clinical studies in human volunteers is also available. Although such investigations are generally reliable for the establishment of exposure-response relationships, they are most often restricted for ethical reasons to the examination of mild, temporary effects (e.g., neurobehavioural or biochemical changes) of short-term exposures in a limited number of subjects. Therefore, such results are often of limited value in assessment of the potential effects of long-term exposure in the general environment.

Epidemiological studies of populations exposed to chemical pollutants in the general environment are most often limited to descriptive epidemiological studies, also referred to as ecological or correlational studies. Generally, in such investigations, mortality or morbidity rates for various diseases in populations in different geographical areas are examined in relation to data on concentrations of pollutants in environmental media (e.g., air or drinking water). Although it is possible to examine large populations in this manner, the lack of data on the exposure of individuals in the population makes it difficult to adjust rigorously for possible confounding factors such as lifestyle factors, which may be as or more important than pollutants in the general environment in the causation of disease. In addition, in such studies, it is difficult to adequately take into account population mobility (that is, movement into and out of the areas under study) or to examine temporal relationships. Although such investigations are useful in generating hypotheses for further testing, they are seldom adequate for identifying cause and effect relationships and are, therefore, not weighted heavily in the determination of "toxic" under paragraph 1l(c) of CEPA.

Analytical epidemiological studies (that is, cohort and case-control studies) in which exposure and outcome are examined in individuals rather than in populations, are more reliable since it is possible to adjust more rigorously for confounding factors. Still, such studies are relatively insensitive in detecting the likely small risks to health which may be associated with exposure to low levels of pollutants in the general environment. Available cohort and case-control studies on the health risks associated with exposure to chemical pollutants are often confined to investigations in the occupational environment, where exposures and potential health risks are greater than those in the general environment. These studies are relevant to the assessment of the weight of evidence for particular effects and for characterization of the exposure-response relationship. The results of such studies are assessed based on several features of study design including estimation of exposure, the role of confounding variables and the measurement of outcome. Assessment of causality of associations observed in such epidemiological studies is evaluated against traditional criteria which include consistency, strength, specificity, exposure-response, the existence of a temporal relationship and biological plausibility.

Owing to the lack of adequate epidemiological data for most existing substances, assessment of "toxic" under paragraph 11(c) of CEPA is most often based on the results of toxicological studies in animal species. In identifying the critical studies for assessment of "toxic", several features of study design are considered including the purity of the compound administered, the size of the study (i.e., how many exposed and control animals there were), whether the study adhered to the principles of good laboratory practice, the relevance of the route of exposure to that of humans, duration of exposure, the number and suitability of the dose levels administered, the extent of examination of various toxicological endpoints and the statistical analysis of the data. The types, site, incidence and severity of effects and the nature of the exposure- or dose-response relationship are also taken into account. Where data indicate that there are significant differences in absorption, distribution, metabolism and elimination of the compound in different animal species, wherever possible, studies in which the species and strain of animal are most similar to man in this regard are used (where relevant human data are available). The consistency of the results of the principal studies are also considered in the assessment of the weight of evidence for an effect (for example, have similar effects been observed in studies in other species or would such effects have been expected based on the structure or properties of the chemical?).

Commonly, the general (i.e., non-occupationally exposed) population in Canada is exposed for a prolonged period (i.e., a lifetime) to low (sometimes non-detectable) concentrations of Priority Substances in the general environment. During the lifetime, there may be especially critical periods where sensitivity is increased (for example, during pregnancy or old age). Consequently, it is the potential for adverse effects on health following the long-term (chronic) exposure or exposure during critical periods (e.g., pregnancy) which are most important in assessing whether substances are "toxic" under paragraph 11(c) of CEPA. Chronic studies in which the chemical has been administered for a considerable portion of the animal's lifespan, or studies in the most sensitive subpopulation (e.g., the embryo or foetus of an exposed mother in developmental studies) are, therefore, preferred as a basis for assessment of "toxic" under paragraph 11(c). Though data on acute or short-term studies in laboratory animals provide useful background information (for identification of target organs or species differences in sensitivity, for example), they are generally not considered sufficient in themselves to assess "toxic" under paragraph 11(c) of CEPA (i.e., a study of subchronic duration or longer is required), unless observed effects in longer term studies are expected to be similar. In some cases where data on the adverse effects of exposure to a Priority Substance are not available from either epidemiological or toxicological studies, potential toxicity may be predicted on the basis of modelling of structure activity relationships, for the purposes of providing information for prioritization of recommendations for additional research.

Information on molecular, biochemical and cellular mechanisms of toxicity as well as metabolic pathways is also collected and evaluated for the assessment of "toxic" under paragraph 11(c) of CEPA. Information on the metabolism of chemical substances (including data on the toxicological effects of potential metabolites) and mechanisms of toxicity is extremely important in assessing the relevance of effects observed in laboratory animals to man. Effects observed in experimental studies may not be relevant to humans if the metabolic pathway or mechanism involved in mediating the toxicity of a particular substance is operative in one or more species of animals but not (or to a much lesser degree) in humans.