Comparison of toxicogenomics and traditional approaches to inform mode of action and points of departure in human health risk assessment of benzo[a]pyrene in drinking water

Abstract

Toxicogenomics is proposed to be a useful tool in human health risk assessment. However, a systematic comparison of traditional risk assessment approaches with those applying toxicogenomics has never been done. We conducted a case study to evaluate the utility of toxicogenomics in the risk assessment of benzo[a]pyrene (BaP), a well-studied carcinogen, for drinking water exposures. Our study was intended to compare methodologies, not to evaluate drinking water safety. We compared traditional (RA1), genomics-informed (RA2) and genomics-only (RA3) approaches. RA2 and RA3 applied toxicogenomics data from human cell cultures and mice exposed to BaP to determine if these data could provide insight into BaP's mode of action (MOA) and derive tissue-specific points of departure (POD). Our global gene expression analysis supported that BaP is genotoxic in mice and allowed the development of a detailed MOA. Toxicogenomics analysis in human lymphoblastoid TK6 cells demonstrated a high degree of consistency in perturbed pathways with animal tissues. Quantitatively, the PODs for traditional and transcriptional approaches were similar (liver 1.2 vs. 1.0 mg/kg-bw/day; lung 0.8 vs. 3.7 mg/kg-bw/day; forestomach 0.5 vs. 7.4 mg/kg-bw/day). RA3, which applied toxicogenomics in the absence of apical toxicology data, demonstrates that this approach provides useful information in data-poor situations. Overall, our study supports the use of toxicogenomics as a relatively fast and cost-effective tool for hazard identification, preliminary evaluation of potential carcinogens, and carcinogenic potency, in addition to identifying current limitations and practical questions for future work.

Neurotoxicity may be an overlooked consequence of benzo[a]pyrene exposure that is relevant to human health risk assessment

“…Neurotoxic effects were observed following oral administration of as little as 0.02 mg/ kg-bw-day (Table 3; e.g., [12]), a LOAEL that is lower than all of the toxic endpoints reviewed by the Cal/EPA (2010). Indeed, our detailed review of BaP-associated effects revealed that neurotoxic endpoints showed the lowest NOAELs overall [13]. These data suggest that BaP neurotoxicity warrants careful consideration for human health risk assessment purposes.…”

Next generation sequencing of benzo(a)pyrene-induced lacZ mutants identifies a germ cell-specific mutation spectrum

“…The mechanisms of BaP mutagenicity have been well characterized and reviewed for somatic tissues1821. The primary mechanism is the faulty replication of unrepaired DNA adducts formed by a BaP metabolite, benzo( a )pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE).…”

Seawater Polluted with Highly Concentrated Polycyclic Aromatic Hydrocarbons Suppresses Osteoblastic Activity in the Scales of Goldfish,Carassius auratus

“…Epidemiological and experimental animal studies associate exposure to BaP with an increased risk of several forms of cancer, including tumors in the forestomach, oral cavity, liver, and lung (Moffat et al, 2015). Furthermore, we can detect NPAHs, such as 1-nitropyrene, 3-nitrobenzanthrone, and 6-nitrochrysene, in samples from the Alexandria and Suez Canal sites.…”

“…Benzo[a]pyrene (BaP) is a kind of PAH well known as a toxic substance and carcinogen (Kizu et al, 2003;Moffat et al, 2015). Epidemiological and experimental animal studies associate exposure to BaP with an increased risk of several forms of cancer, including tumors in the forestomach, oral cavity, liver, and lung (Moffat et al, 2015).…”