Cancer risk assessment defaults

Overall, cancer risk assessment involves the four steps of hazard identification, dose-response, exposure assessment, and risk characterization. The dose-response curve established for cancer potency derivation for a chemical is based on evaluation of data on the carcinogenicity and dose-response characteristics of the chemical. The pharmacokinetics and mechanistic data evaluation (e.g., genotoxic or nongenotoxic) and a dose-response review of all adequate bioassays are conducted to determine, if target dose estimates or a dose-response model different from the default may be suggested. 

These few examples reveal the practical applications of some of the emerging scientific views regarding the actions of chemicals that induce cancers in animals. The development of information to test the LNT hypothesis (the standard default) is an important area of research that can not only improve the basis for risk assessment, but can also more generally advance knowledge of carcinogenic processes. 

The National Research Council (NRC) published a report, Science and Judgment in Risk Assessment, that critiqued the current approaches to characterizing human cancer risks from exposure to chemicals. One issue raised in the report relates to the use of default options for assessing of cancer risks. These general guidelines can be used for risk assessment when specific information about a chemical is absent. Research on 1,3-butadiene indicates that two default options may no longer be tenable Humans are as sensitive as the most sensitive animal species and the rate of metabolism is a function of body surface area rather than inherent species differences in metabolic capacity. 

In some instances, the specific data on a given chemical or pollutant source will replace conservative defanlt options used in earlier assignments. The report includes two authored appendices that address issues related to the use of default options and their replacement by specific scientific information. One appendix (by Finkel) advocates a principle of plausible conservatism for choosing and altering default options and in making cancer risk estimates. The second appendix (by McClellan and North) advocates the full use of scientific information in the risk assessment process. 

The analysis need not be confined to the estimation of a standard that uses conventional methods of extrapolation (e.g., default assessment factors). It might usefully be accompanied by an analysis of the consequences of exceeding a particular standard. If a standard is proposed that sits within the range of available toxicological or ecotoxicological data or close to the lower limit of experimental data, then we should try to predict what impact an exceedance will have (e.g., excess cancer risk, proportion of species affected, or number of individuals affected). 

In this approach it is proposed that mechanistic data be used to support the assessment of cancer risk at low (environmental or occupational) exposure levels, in the absence of human or laboratory animal tumor data in this exposure range. This represents a significant advance over previous practice whereby, for mutagenic chemicals, a default approach was used that required a linear extrapolation from... 

In the absence of human data (the most preferred data for risk assessment), the dose-response assessment for either cancer or noncancer toxicity is determined from animal toxicity studies using an animal model that is relevant to humans or using a critical study and species that show an adverse effect at the lowest administered dose. The default assumption is that humans may be as sensitive as the most sensitive experimental species. 

---