Informal Comments of the National Institute for Occupational Safety and Health on the June 2012

Interagency Science Consultation draft 

Toxicological Review of Benzo[a]pyrene 

July 10, 2012

The National Institute for Occupational Safety and Health (NIOSH) thanks the U.S. Environmental 

Protection Agency (EPA) for the opportunity to comment on the June 2012 Interagency Science 

Consultation draft Toxicological Review of Benzo[a]pyrene and June 2012 EPA Proposed Draft 

Charge to the Science Advisory Board for the IRIS Toxicological Review of Benzo[a]pyrene prepared 

in support of summary information on the Integrated Risk Information System (IRIS). 

Human chemical carcinogenesis is a complex process and rarely does a single chemical exposure occur 

(as noted in the draft document.) Benzo[a]pyrene (BaP) has been known for many years as a complete 

carcinogen in the mouse skin model. The presented weight of evidence supports a carcinogenic 

mechanism in humans that involves metabolic activation and ultimately gene mutation. 

1.a) NIOSH recommends that the discussion of human interindividual variation be expanded. Although

it is mentioned in relation to CYP1A1 variation, there are many more studies than those cited and little 

agreement among them. In addition, gene induction varies considerably. For example, NIOSH authors 

reported a 26.6—100 fold variation in induction of CYP1A1 by BaP and a 12.4—40 fold variation in 

CYP1B1 induction among 20 different human samples [Keshava et al. 2005; John et al. 2010]. 

b) The statement “...there is strong evidence that the key precursor events of benzo[a]pyrene’s mode of 

action are likely to be associated with tumor formation in humans” is somewhat overstated (p. 1-72). 

Tobacco smoke is a carcinogen and a complex chemical mixture. The principal target tissue in humans 

is the lung, so when lung tumors are examined for “key precursor events” (pp. 1-70—1-72), a wide 

variety of biomarkers are found and some resemble those expected from pure BaP exposure.

c) The issue of DNA repair capability needs to be considered carefully and expanded (one paragraph on 

these issues appears on page 1-68.)

Given the observations above concerning interindividual variation (in carcinogen metabolism, 

activation, detoxification and DNA repair), it seems imperfect for a carcinogen like BaP, which always 

appears in nature as a component of a complex mixture, to attach a “Reference Dose” (POD) for 

humans.

2. NIOSH has some concern about the method selected for interspecies scaling of dermal cancer risks.

The Knafla et al. [2011] study cited by EPA concluded that the interspecies scaling method EPA is using 

for dermal carcinogenicity, scaling according to body weight3/4, was not applicable to interspecies 

scaling of dermal cancer risks. NIOSH notes that EPA has stated appropriately that “An established 

methodology does not exist to adjust for interspecies differences in dermal toxicity at the point of 

contact” (p. 2-39, Table 2-12). Furthermore, EPA included the choice of body weight3/4 for interspecies 

scaling of the dermal slope factor as a charge question for peer reviewers (question 3 under “Dermal 

Slope Factor” on p. 5 of the draft charge to reviewers). NIOSH believes the question of interspecies 

scaling for dermal cancer risk is an important one, and supports EPA in raising this issue as a charge 

question to the peer reviewers.

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Typographical error noted in Supplemental information, page B-3 title and in Table of contents, p. iii: 

“reponse” 

References (.pdfs can be provided)

John K, Divi RL, Keshava C, Orozco CC, Schockley ME, Richardson DL, Poirier MC, Nath J, Weston 

A [2010]. CYP1A1 and CYP1B1 gene expression and DNA adduct formation in normal human 

mammary epithelial cells exposed to benzo[a]pyrene in the absence or presence of chlorophyllin. 

Cancer Lett 292(2):254-260.

Keshava C, Divi RL, Whipkey DL, Frye BL, McCanlies E, Kuo M, Poirier MC, Weston A [2005]. 

Induction of CYP1A1 and CYP1B1 and formation of carcinogen–DNA adducts in normal human 

mammary epithelial cells treated with benzo[a]pyrene. Cancer Lett 221(2):213-224.