Application of benzo(a)pyrene and coal tar tumor dose-response data to a modified benchmark dose method of guideline development

Abstract

Assessment of cancer risk from exposure to polycyclic aromatic hydrocarbons (PAHs) has been traditionally conducted by applying the conservative linearized multistage (LMS) model to animal tumor data for benzo(a)pyrene (BaP), considered the most potent carcinogen in PAH mixtures. Because it has been argued that LMS use of 95% lower confidence limits on dose is unnecessarily conservative, that assumptions of low-dose linearity to zero in the dose response imply clear mechanistic understanding, and that "acceptable" cancer risk rests on a policy decision, an alternative cancer risk assessment approach has been developed. Based in part on the emerging benchmark dose (BMD) method, the modified BMD method we used involves applying a suite of conventional mathematical models to tumor dose-response data. This permits derivation of the average dose corresponding to 5% extra tumor incidence (BMD0.05) to which a number of modifying factors are applied to achieve a guideline dose, that is, a daily dose considered safe for human lifetime exposure. Application of the modified BMD method to recent forestomach tumor data from BaP ingestion studies in mice suggests a guideline dose of 0.08 microg/kg/day. Based on this and an understanding of dietary BaP, and considering that BaP is a common contaminant in soil and therefore poses human health risk via soil ingestion, we propose a BaP soil guideline value of 5 ppm (milligrams per kilogram). Mouse tumor data from ingestion of coal tar mixtures containing PAHs and BaP show that lung and not forestomach tumors are most prevalent and that BaP content cannot explain the lung tumors. This calls into question the common use of toxicity equivalence factors based on BaP for assessing risk from complex PAH mixtures. Emerging data point to another PAH compound--H-benzo(c)fluorene--as the possible lung tumorigen.

Figure 1. Suite of models fitted to BaP dose–response data (mouse forestomach tumors) reported by Culp et al. (1998). (A) MLE fitting of models except the truncated normal, which could not be fitted. (B) The extra-risk dose curves of (A) in the low-dose region around the 0.05 risk level and averaged dose at 0.362 mg/kg/day.

Figure 2. Comparison of dose responses for tumors reported by Culp et al. (1998), plotted for BaP alone and BaP content of coal tar mixtures. (A) Forestomach tumors. (B) Lung tumors.