Monocyclic aromatic amines as potential human carcinogens: old is new again The MIT Faculty has made this article openly available. Please share how this access benefits you. Your story matters. Citation Skipper, P. L. et al. “Monocyclic aromatic amines as potential human carcinogens: old is new again.” Carcinogenesis 31 (2009): 50-58. Web. 2 Nov. 2011. As Published http://dx.doi.org/10.1093/carcin/bgp267 Publisher Oxford University Press Version Author's final manuscript Citable link http://hdl.handle.net/1721.1/66896 Terms of Use Creative Commons Attribution-Noncommercial-Share Alike 3.0 Detailed Terms http://creativecommons.org/licenses/by-nc-sa/3.0/ Carcinogenesis vol.31 no.1 pp.50–58, 2010 doi:10.1093/carcin/bgp267 Advance Access publication November 3, 2009 Monocyclic aromatic amines as potential human carcinogens: old is new again Paul L.Skipper, Min Young Kim, H.-L.Patty Sun, Gerald phenotype tend to support the biochemical mechanisms inferred from N.Wogan and Steven R.Tannenbaumà experimental studies (6). It appears that, for this class of chemical carcinogens, the linkage between the experimental setting and the Department of Biological Engineering, Massachusetts Institute of human condition is as strong as any. Yet, there remains a conundrum: Technology, Cambridge, MA 02139, USA outside the occupational setting there appears to be far too little ÃTo whom correspondence should be addressed. Tel: þ1 617 253 6792; exposure to any of the known human bladder carcinogens to account Fax: þ1 617 252 1787; for the observed incidence rates. Email: [email protected] Various possibilities may be considered for resolving this conun- Alkylanilines are a group of chemicals whose ubiquitous pres- drum. The models used for extrapolating from high to low dose may ence in the environment is a result of the multitude of sources underestimate potency at human exposure levels. There may be envi- from which they originate. Exposure assessments indicate that ronmental exposures to known compounds that are largely cryptic or most individuals experience lifelong exposure to these com- there may be amines in the environment that have not yet been iden- pounds. Many alkylanilines have biological activity similar to tified. Unanticipated synergies among multiple exposures may occur. that of the carcinogenic multi-ring aromatic amines. This review Other possibilities no doubts exist. Because of their environmental provides an overview of human exposure and biological effects. prevalence, one relatively unexplored group of aromatic amines, the It also describes recent investigations into the biochemical mech- alkylanilines, may be significantly involved in one or more of these anisms of action that lead to the assessment that they are most explanations. In this paper, we will review much of the research on probably more complex than those of the more extensively in- alkylanilines that addresses the question of why they could be playing vestigated multi-ring aromatic amines. Not only is nitrenium ion an important role in human cancer. chemistry implicated in DNA damage by alkylanilines but also reactions involving quinone imines and perhaps reactive oxygen species. Recent results described here indicate that alkylanilines Environmental prevalence can be potent genotoxins for cultured mammalian cells when In considering the importance of any specific chemical carcinogen activated by exogenous or endogenous phase I and phase II or class of carcinogens to human disease incidence, weight must be xenobiotic-metabolizing enzymes. The nature of specific DNA given to the extent to which the compounds are distributed in the damage products responsible for mutagenicity remains to be environment. Alkylanilines, as a class, appear to be distributed identified but evidence to date supports mechanisms of activa- widely, making exposure to them nearly ubiquitous. Early efforts tion through obligatory N-hydroxylation as well as subsequent at exposure assessment were predicated on the fact that alkylanilines conjugation by sulfation and/or acetylation. A fuller under- are present in tobacco smoke (7–9). Accordingly, indoor spaces standing of the mechanisms of alkylaniline genotoxicity is contaminated with tobacco smoke exhibited higher levels of alkyla- expected to provide important insights into the environmental nilines than uncontaminated spaces (8,10). Outdoor air was gener- and genetic origins of one or more human cancers and may ally lower with exceptions that may be attributable to industrial reveal a substantial role for this group of compounds as potential sources (10). Exposure assessment based on hemoglobin adduct human chemical carcinogens. levels also indicates that tobacco smoke is a significant, if not pre- dominant, source for many alkylanilines (11,12). In both studies, 2,6-dimethylaniline (2,6-DMA) was an exception, being actually higher in non-smokers than smokers in a study conducted in Italy Introduction (11). Much higher levels (7- to 8-fold) of 3,5-dimethylaniline (3,5- DMA) were also observed in non-smokers in the Italian population. Aromatic amines are a class of organic compounds that include many This finding attains greater significance in light of a recent investi- members that are carcinogenic, both experimentally in the research gation in Canada (13) that found levels of 3,5-DMA in indoor and setting and experientially in human life. The carcinogenesis literature outdoor air that are two to three orders of magnitude higher than documents innumerable studies demonstrating that administration of those reported elsewhere. a considerable variety of aromatic amines to experimental animals of Exposure assessment through hemoglobin adduct analysis has different species induces cancers in those animals (1). The epidemi- now been extended to include non-tobacco sources in the USA ological literature leaves little doubt that a specific few aromatic (12), Italy (11), Germany (14) and most recently by us in China amines are the cause of bladder cancer in occupationally exposed (unpublished results). In all of these studies, there have been virtu- persons and there is a convincing argument to be made that exposure ally no subjects that do not have hemoglobin adducts of all of the to aromatic amines via tobacco smoke is a major, if not predominant, compounds investigated. Results tend to be comparable: while there factor in causing bladder cancer in smokers (2). may be a considerable range of values among individual subjects, The biochemical mechanisms by which aromatic amines might mean values tend to fall within a range of ,10-fold. The inescapable induce cancers have been investigated extensively and are now conclusion from these results is that environmental prevalence of thought to be reasonably well understood (3–5). Human population many alkylanilines is extensive and that exposure to them is not studies that have incorporated measures of metabolic genotype and confined to limited population subgroups such as the occupationally exposed. Abbreviations: 4-ABP, 4-aminobiphenyl; CHO, Chinese hamster ovary; 2,6- Figure 1 illustrates most of the important routes by which alkylani- DMA, 2,6-dimethylaniline; 3,5-DMA, 3,5-dimethylaniline; 3-EA, 3-ethylani- lines come to be present in the environment. It is based on the com- line; NAT, N-acetyltransferase; NER, nucleotide excision repair; ROS, reactive prehensive information about production and possible releases into oxygen species; TGHQ, 2,3,5-tris-(glutathion-S-yl)hydroquinone. the environment of specific alkylanilines that can be found in the Ó The Author 2009. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Alkylanilines as potential human carcinogens chemicals is thought to have ceased, revealed a continuing excess of tobacco colorants smoke bladder cancer among exposed workers. Experimental carcinogenicity A comprehensive review of the carcinogenicity of alkylanilines is fugitive outside the scope of this paper mainly because so many of the results, pesticides NH2 emissions while suggestive of carcinogenic potential, are largely inconclusive. R ,R ,…R 1 2 n Furthermore, the National Toxicology Program has recently con- ducted a review of the literature as part of its process for nominating several alkylanilines for future study. The review can be found in the motor drugs nominating document at http://ntp.niehs.nih.gov/ntp/noms/Support_ fuels Docs/Alkylanilines060809.pdf. The document includes genotoxicity data as well and therefore covers an expanded set of 14 compounds. Fig. 1. Environmental sources of alkylanilines. Here, we will focus on the two compounds for which the International Agency for Cancer has found sufficient evidence to categorize them as either carcinogenic to humans (o-toluidine; Group 1) or possibly car- cinogenic to humans (2,6-DMA; Group 2B). Hazardous Substances Data Bank (http://toxnet.nlm.nih.gov/cgi-bin/ As described by the International Agency for Cancer, ‘ortho-tolu- sis/htmlgen?HSDB) as well as the references cited above. idine was tested for carcinogenicity as its hydrochloride salt in two experiments in mice and in three experiments in rats and as the free base in one limited experiment in hamsters. After oral administration Evidence for carcinogenicity in a population-based study