Human Health Risk Assessment for Priority Substances

3.0 Approaches for the Assessment of "Toxic" under paragraph 11(c) of CEPA - Single Substances

3.1 Assessment of Population Exposure

Exposure to environmental substances may occur by inhalation, ingestion and/or dermal absorption from air, water, food, soil and through the use of consumer products. Estimation of the total daily intake (usually expressed as mg/kg body weight/day) from all sources is critical in assessing the true magnitude of risk associated with exposure to substances in the general environment. This "multimedia" approach also sets the stage for any subsequent development of measures which are most effective for human health protection by identifying the relative magnitude of the contribution of each pathway of exposure to total daily intake.

Standardized reference values for body weights, the volume of air breathed, quantities of food, water and soil ingested and, to the extent possible, information on behavioural patterns of the exposed population(s) form an integral part of the estimation of exposure from all sources. A description of the reference values for these parameters, used in estimating the total daily intake of Priority Substances by five discrete age groups in the general population in Canada, and the rationale for their selection are presented in Appendix A.

It should be emphasized that the reference values tabulated in Appendix A and concentrations in environmental media used in the population exposure estimates are representative for average members of the general population of Canada. Owing to the often considerable variation in mean concentrations of chemical substances in environmental media measured at different locations, the estimated daily intakes from various media for each of the age groups are generally expressed as a range of mean values. Exposure of a significant proportion of the population will be incorporated within these ranges. In addition, exposure of some segments of the population which may be greater than those for the population at large (i.e., "high-exposure subgroups"), is also taken into account, where considered appropriate and where sufficient data are available. For example, exposures via one or more routes to some substances may be elevated for persons living in the vicinity of point sources (such as industrial emissions), depending on the form in which these substances are released and their subsequent environmental transport and transformation. The intake of some substances by subsistence hunters or fishermen may also be elevated due to accumulation in the game species which they consume. It should be noted, however, that although relevant data concerning occupational exposure, paraoccupational exposure (for hobbyists, for example), substance abuse and smoking are sometimes reviewed and presented in assessments for Priority Substances, they are not considered in the estimation of total daily intake, since such exposures are highly variable, often not typical of most of the general population and more appropriately addressed under statutes other than CEPA. Exposure from consumer products is taken into account, however, primarily through estimation of intake from indoor air.

Selection of "high-exposure subgroups" for which total daily intakes are estimated is determined on a case-by-case basis. In addition to the magnitude of the estimated intake for various subgroups, the most important factor weighted in this determination is the size of the exposed population. For example, elevated levels to which few individuals are exposed in isolated locales as a result of intermittent spills or leakage are not considered relevant to estimation of exposure for the general population. Additional factors considered in the selection of relevant "high-exposure subgroups" are use patterns, environmental partitioning of the substance, the major routes of exposure, and availability of quantitative data on concentrations in relevant media and consumption.

In general, information on the toxicokinetics of a Priority Substance is not incorporated into the estimated total daily intakes since, in the assessment of "toxic", they are generally compared to tolerable daily intakes or quantitative estimates of cancer potency that are based on nominal doses to which animals or humans in the critical toxicological or epidemiological studies are exposed.

3.2 Assessment of Effects

Different approaches have been adopted to assess whether a Priority Substance is "toxic" under paragraph 11(c) of CEPA, depending on whether the critical effect is considered to have or not to have a threshold ("threshold toxicants" or "non-threshold toxicants", respectively). (The critical effect is defined as the biologically significant effect expected to occur at the lowest dose or concentration). For many types of toxic effects (i.e., organ-specific, neurological/behavioural, immunological, epigenetic carcinogenesis, reproductive or developmental), it is generally considered that there is a dose or concentration below which adverse effects will not occur (i.e., a threshold). For other types of toxic effects it is assumed, but not proven, that there is some probability of harm at any level of exposure (i.e., that no threshold exists). At the present time, the latter assumption is generally considered to be appropriate only for mutagenesis and genotoxic carcinogenesis.

Chemical substances are classified, therefore, with respect to their potential carcinogenicity and mutagenicity to humans; this is accomplished on the basis of rigorous examination of the quantity, quality and nature of the results of available toxicological and epidemiological studies. The criteria by which Priority Substances are classified based on their weight of evidence of carcinogenicity and mutagenicity are outlined in Appendices B and C, respectively.

3.2.1 "Non-Threshold Toxicants"

For those substances for which the critical effect is assumed to have no threshold (i.e., currently restricted to mutagenesis and genotoxic carcinogenesis), it is assumed that there is some probability of harm to human health at any level of exposure, and consequently it is not appropriate to calculate a dose below which adverse effects are not expected to occur.

Therefore, substances classified in Groups I ("Carcinogenic to Humans") or II ("Probably Carcinogenic to Humans") in Appendix B are considered to be "toxic" under paragraph 11(c) of CEPA.

Substances classified in Groups I ("Human Germ Cell Mutagen") or II ("Probable Human Germ Cell Mutagen") of Appendix C for which the weight of evidence of carcinogenicity is weak, may be considered to be "toxic" under paragraph 11(c) of CEPA.

For such substances, mathematical models are often used to extrapolate data on the exposure-or dose-response relationship derived from experimental studies in animal species or epidemiological studies (generally in workers) to estimate the risk at concentrations to which the general population is exposed. There are numerous uncertainties in this approach, which generally involves linear extrapolation of results over several orders of magnitude, often in the absence of relevant data on mechanisms of tumour induction or differences in toxico-kinetics and -dynamics between the relevant experimental animal species and humans.

For assessment of "toxic" under paragraph 11(c) of CEPA for non-threshold toxicants, it is considered inappropriate to specify a concentration or dose associated with a negligible or de minimis level of risk (such as a lifetime cancer risk of 1 in 1 million) by low-dose extrapolation procedures, primarily since this would involve inclusion of considerations other than those based on science at this stage (i.e., making a societal judgement about what level constitutes de minimis risk). There is no single "correct" value which adequately characterizes de minimis risk associated with a concentration or dose below which risks are acceptable and above which they are not; rather, the risk at low doses or concentrations is assumed to be a continuum, with reduction of exposure leading to an incremental reduction of risk and increases in exposure leading to incremental increases in risk. In addition, in view of the considerable uncertainties of current low-dose extrapolation procedures, it is also considered inappropriate to specify risks in terms of predicted incidence or numbers of excess deaths per unit of the population.

However, it is recognized that the incremental risks associated with exposure to low levels of such substances, although difficult to characterize, may be sufficiently small so as to be essentially negligible compared with other risks encountered in society and that on this basis, control action to reduce exposure may not be justified. Decisions concerning the need for, and development of, control strategies may be made only following a judicious balancing of the estimated risks against the associated costs and feasibility of controls, and/or benefits to society (i.e., in stages subsequent to assessment of "toxic" under the Act such as strategic options analysis).

To characterize risk and provide guidance in establishing priorities for further action following assessment of "toxic" under the Act, where possible, quantitative estimates of the carcinogenic and mutagenic potency of compounds classified in Groups I and II of Appendices B and C are compared to the estimated daily intake of the Priority Substance by the general population (or certain high-exposure subgroups) in Canada, or to concentrations in specific relevant environmental media (referred to as the Exposure/Potency Index or EPI). Potency is expressed as the concentration or dose which induces a 5% increase in the incidence of, or deaths due to, tumours or heritable mutations considered to be associated with exposure¹. It may be based on tumours observed in epidemiological studies (generally) in occupationally exposed human populations or those considered relevant to humans as observed in bioassays in laboratory animals. The estimates of potency are generally restricted to effects for which there has been a statistically significant increase in incidence and a dose-response relationship, characterized using appropriate mathematical models (e.g., multistage).

Any model which fits the empirical data well is likely to provide a reasonable estimate of the potency; choice of the model may not be critical since estimation is within the observed dose range, thereby avoiding the numerous uncertainties associated with low-dose extrapolation. The value of 5% is arbitrary; selection of another value would not impact on the relative magnitudes of the Exposure/Potency Indices (EPIs) for each of a range of compounds. The priority for further action (i.e., analysis of options to reduce exposure) is considered to be high for EPIs of approximately 2.0 H 10^-4 or greater; for EPIs within the range of greater than or equal to approximately 2.0 H 10^-6 to less than approximately 2.0 H 10^-4, it is considered to be moderate and for EPIs less than approximately 2.0 H 10^-6, it is considered to be low. That is, when estimated exposure is only a very small proportion of the concentration or dose which induces a 5% increase in tumours, the priority for analysis of options to reduce exposure is low.

Wherever possible and if considered appropriate, information on pharmacokinetics, metabolism and mechanisms of carcinogenicity and mutagenicity is incorporated into the quantitative estimates of potency derived particularly from studies in animals (to provide relevant scaling of potency for human populations).

Obviating the establishment of a single de minimis risk level enables the assessment of "toxic" for "non-threshold toxicants" to be based to the extent possible on scientific considerations. This approach is also consistent with the objective that exposure to "nonthreshold toxicants" should be reduced to the extent possible.

3.2.2 "Threshold Toxicants"

The approach to assessment of "toxic" for substances classified in Groups IV ("Unlikely to Be Carcinogenic to Humans"), V ("Probably Not Carcinogenic to Humans"), or VI ("Unclassifiable with Respect to Carcinogenicity in Humans") based on the criteria in Appendix B, is that adopted for "threshold toxicants" as described in this section. Threshold toxicants are those for which the critical effect is not considered to be cancer or a heritable mutation. It is recognized, however, that for at least one of these categories (Group VI), adoption of this approach is sometimes a function more of the lack of available data on carcinogenicity than certain knowledge of the critical effect. Though this may appear to be less than conservative, tolerable daily intakes for compounds in this group are developed on the basis of very large uncertainty factors (to account for inadequacies of the database), with the objective of providing protection for potential carcinogenicity.

Where possible, a dose (or concentration) of a chemical substance that does not produce any (adverse) effect [i.e., "no-observed-(adverse)-effect-level" (NO(A)EL)²] for the critical endpoint is identified, usually from toxicological studies involving laboratory animals, but sometimes from epidemiological studies of human populations. If a value for the NO(A)EL cannot be ascertained, a lowest-observed-(adverse)-effect-level (LO(A)EL) is used. The nature and severity of the critical effect (and to some extent, the steepness of the dose-response curve) are taken into account in the establishment of the NO(A)EL or LO(A)EL. For example, the concentration or dose which induces a transient increase in organ weight without accompanying biochemical or histopathological effects would generally be considered a LOEL. If there are accompanying adverse histopathological effects in the target organ, the concentration or dose at which these effects were observed would be considered a LOAEL.

An uncertainty factor is applied to the NO(A)EL or LO(A)EL to derive a Tolerable Daily Intake or Concentration (TDI or TDC)³, the intake or concentration to which it is believed that a person can be exposed daily over a lifetime without deleterious effect⁴. Ideally, the NO(A)EL is derived from a chronic exposure study involving the most relevant or sensitive species (where possible, determined based on data on species differences in pharmacokinetic parameters or mechanism of action) or on investigations in the most sensitive subpopulation⁵ (e.g., the embryo or foetus in developmental studies) in which the route of administration (in studies with laboratory animals) is similar to that by which humans are principally exposed. Tolerable Daily Intakes or Concentrations are not generally developed on the basis of data from acute or short-term studies (unless observed effects in longer term studies are expected to be similar), although they are occasionally based on data from subchronic studies in the absence of available information in adequately designed and conducted chronic toxicity studies, in which case an additional factor of uncertainty is included. Exceptionally, in cases where a NO(A)EL or LO(A)EL cannot be identified in studies by the route of exposure by which humans are principally exposed, a NO(A)EL or LO(A)EL from a bioassay by another route of exposure may be used where appropriate, incorporating relevant pharmacokinetic data.

The uncertainty factor is derived on a case-by-case basis, depending principally on the quality of the database. Generally, a factor of 1 to 10 is used to account for intraspecies variation and interspecies variation⁶. An additional factor of 1 to 100 is used to account for inadequacies of the database which include but are not necessarily limited to, lack of adequate data on developmental, chronic or reproductive toxicity, use of a LO(A)EL versus a NO(A)EL and inadequacies of the critical study. An additional uncertainty factor ranging between 1 and 5 may be incorporated where there is sufficient information to indicate a potential for interaction with other chemical substances commonly present in the general environment. If the chemical substance is essential or beneficial for human health, the dietary requirement is also taken into consideration in derivation of the Tolerable Daily Intake or Concentration. Exceptionally, in deriving a TDI or TDC for severe effects (e.g., teratogenicity), an additional uncertainty factor of 1 to 10 may be incorporated. Numerical values of the uncertainty factor normally range from 1 to 10,000. Uncertainty factors greater than 10,000 are not applied since the limitations of such a database are sufficient to preclude development of a reliable TDI or TDC. In some cases, where the uncertainty factor is less than 10,000 but there are limitations in the protocol of the critical study, a "tentative TDI" or "tentative TDC" may be established.

The value of the TDI, TDC, "tentative TDI" or "tentative TDC" is compared to the estimated total daily intake of a chemical substance by the various age groups of the population of Canada and, in some cases, certain high-exposure subgroups or to concentrations in relevant environmental media.

If the estimated total daily intake of a chemical substance by the various age groups of the Canadian population (or certain subgroups) or concentrations in relevant environmental media exceed(s) or could exceed the TDI, TDC, "tentative TDI" or "tentative TDC", the substance is considered to be "toxic" under paragraph 11(c) of CEPA; if the estimated daily intake or concentrations in relevant environmental media are less than the TDI, TDC, "tentative TDI" or "tentative TDC", the substance is not considered to be "toxic" under the Act.

For those "threshold toxicants" considered to be "toxic" under paragraph 11(c) of CEPA, the estimated total daily intake of the substance by the general population in Canada or concentrations in relevant environmental media are compared to the NO(A)EL or LO(A)EL on which the TDI or TDC is based, to provide guidance in establishing priorities for further action following assessment of "toxic" under the Act.

An alternative approach, which may be used where data permit, involves estimation of the "benchmark dose", a model-derived estimate of a particular incidence level (e.g., 5%) for the critical effect. More specifically, the benchmark dose is the effective dose (or its lower confidence limit) that produces a certain increase in incidence above control levels. The benchmark dose is derived by modelling the data in the observed range and selecting the point on the curve (or its upper confidence limit) corresponding to a specified increase in the incidence of an effect. Any model which fits the empirical data well is likely to provide a reasonable estimate of the benchmark dose and choice of the model may not be critical since estimation is within the observed dose range. The advantages of the benchmark dose are that it takes into account the slope of the dose-response curve, the size of the study groups and the variability in the data in establishment of the true threshold.

3.2.3 "Possible Non-Threshold Toxicants"

Substances classified as "Possibly Carcinogenic to Humans" (Group III in Appendix B) are generally assessed in a manner similar to "threshold toxicants"; the determination of "toxic" under CEPA is made by comparing the total daily intake by the various age groups of the Canadian population or concentrations in relevant environmental media with the value derived for the TDI or TDC as described for Groups IV to VI above. Exceptionally, however, in deriving the TDI or TDC for substances classified as "Possibly Carcinogenic to Humans", an additional uncertainty factor (ranging between 1 and 10) may be incorporated to account for the limited evidence of carcinogenicity. In some cases where considered appropriate⁷, quantitative estimates of the carcinogenic potency of these substances (or the potency to induce heritable mutations) are compared to the estimated daily intake by the general population in Canada, or to concentrations in relevant environmental media, to characterize risk and provide guidance in establishing priorities for further action following assessment of "toxic" under the Act.

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