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 μg/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—7H-benzo(c)fluorene—as the possible lung tumorigen.

PAHs Underfoot: Contaminated Dust from Coal-Tar Sealcoated Pavement is Widespread in the United States

“…ΣPAH concentrations in these samples (5800 and 9600 mg/kg) exceed those in all of the other dust samples collected for this study. Concentrations of benzo[a]pyrene, considered the most potent carcinogen in PAH mixtures (27), in these samples are 597 and 357 mg/ kg; the median of 477 mg/kg is more than twice the median of 201 mg/kg (computed as the median of the median value for each city) in dust from sealcoated pavement for the six central and eastern cities. The median concentration of benzo[a]pyrene in the two driveway samples is 5300 times greater than the benzo[a]pyrene generic soil screening level (SSL) of 0.09 mg/kg used by the U.S. Environmental Protection Agency Superfund Program (28) and is 95 times greater than a less conservative benzo[a]pyrene soil guideline of 5 mg/kg proposed by Fitzgerald et al (27).…”

“…Concentrations of benzo[a]pyrene, considered the most potent carcinogen in PAH mixtures (27), in these samples are 597 and 357 mg/ kg; the median of 477 mg/kg is more than twice the median of 201 mg/kg (computed as the median of the median value for each city) in dust from sealcoated pavement for the six central and eastern cities. The median concentration of benzo[a]pyrene in the two driveway samples is 5300 times greater than the benzo[a]pyrene generic soil screening level (SSL) of 0.09 mg/kg used by the U.S. Environmental Protection Agency Superfund Program (28) and is 95 times greater than a less conservative benzo[a]pyrene soil guideline of 5 mg/kg proposed by Fitzgerald et al (27). A summary of research on mutagenic hazards of settled house dust concluded there was "substantially elevated risk" corresponding to the 95th percentile or greater PAH content in the dust as summarized from 18 studiessthe 95th percentile concentration of benzo[a]pyrene was 13.0 mg/kg (29).…”

Risk of the Development of Perceptive Hearing Loss Among the Employees of Aircraft Repair Plants Exposed to Noise

“…Different models may all fit the data reasonably well (top), but yield highly divergent response estimates at low doses (bottom). The data and models are taken from Fitzgerald et al (2004).…”

ERα phenotype, estrogen level, and benzo[a]pyrene exposure modulate tumor growth and metabolism of lung adenocarcinoma cells

“…Fitzgerald et al proposed a dose-response relationship in which BaP intake at 6 mg/kg/day would induce forestomach tumors in about 90% of mice [32]. Young adult nude mice weighed around 20 g. Therefore, we selected four doses of BaP, 0, 0.2, 0.8, and 1.6 mg/week, to test the effects of BaP on xenograft tumor growth of CL1-5 cells.…”