Using immunotoxicity information to improve cancer risk assessment for polycyclic aromatic hydrocarbon mixtures

Estimating cancer risk from environmental mixtures containing polycyclic aromatic hydrocarbons (PAHs) is challenging. Ideally, each mixture would undergo toxicity testing to derive a cancer slope factor (CSF) for use in site-specific cancer risk assessments. However, this whole mixture approach is extremely costly in terms of finances, time, and animal usage. Alternatively, if an untested mixture is "sufficiently similar" to a well-characterized mixture with a CSF, the "surrogate" CSF can be used in risk assessments. We propose that similarity between 2 mixtures could be established using an in vitro battery of genotoxic and nongenotoxic tests. An observed association between carcinogenicity and immunosuppression of PAHs suggests that the addition of immune suppression assays may improve this battery. First, using published studies of benzo[a]pyrene (BaP) and other PAHs, we demonstrated a correlation between the derived immune suppression relative potency factors (RPFs) for 9 PAHs and their respective cancer RPFs, confirming observations published previously. Second, we constructed an integrated knowledge map for immune suppression by BaP based on the available mechanistic information. The map illustrates the mechanistic complexities involved in BaP immunosuppression, suggesting that multiple in vitro tests of immune suppression involving different processes, cell types, and tissues will have greater predictive value for immune suppression in vivo than a single test. Based on these observations, research strategies are recommended to validate a battery of in vitro immune suppression tests that, along with tests for genotoxic and other nongenotoxic modes of cancer action, could be used to establish "sufficient similarity" of 2 mixtures for site-specific cancer risk assessments.