Mutagenesis vol. 26 no. 5 pp. 583–584, 2011 doi:10.

1093/mutage/ger033
Advance Access Publication 1 July 2011

COMMENTARY
Styrene exposure and risk of cancer

James Huff* and Peter F. Infante1 which indicates evidence of a credible but not a clear demonstra-
National Institute of Environmental Health Sciences, Research Triangle Park,
tion of a causal association with lymphatic/hematopoietic
111 T.W.Alexander Drive, NC 27709, USA and 1Environmental and neoplasms in humans. Teixeira et al. (2), however, dismissed
Occupational Health, School of Public Health and Health Services, George IARC’s Working Group evaluation in 2002 (5) by iterating from
Washington University, Washington, DC 20037, USA. the 2009 Boffetta et al. (6) styrene review paper ‘that no consistent
*
To whom correspondence should be addressed. Tel: +1 919 541 3780; increased risk of any cancer among workers exposed to styrene
Fax: +1 919 541 5002; Email: huff1@niehs.nih.gov was found. Indeed, Boffetta et al. (6) concluded that the available
Received on December 8, 2010; revised on April 13, 2011;
epidemiologic evidence does not support a causal relationship
accepted on April 26, 2011 between styrene exposure and any type of human cancer’ (2).
The Boffetta et al. (6) review on behalf of Styrene Information
Styrene is widely used in the manufacture of synthetic and Research Center, a styrene industry organisation, was
rubber, resins, polyesters and plastics. Styrene and the presented by co-author P. Cole to the National Toxicology
primary metabolite styrene-7,8-oxide are genotoxic and Program’s (NTP) Board of Scientific Counsellors open-to-the-
carcinogenic. Long-term chemical carcinogenesis bioassays
public Peer Review of styrene (7). The NTP independent Board
showed that styrene caused lung cancers in several strains
was not swayed or particularly impressed with the analysis and
of mice and mammary cancers in rats and styrene-7,8-
conclusions of the Boffetta et al. review (6,7). Moreover, in 2009
oxide caused tumours of the forestomach in rats and mice
(1), the US Department of Health and Human Service’s NTP
and of the liver in mice. Subsequent epidemiologic studies
declared ‘Styrene is reasonably anticipated to be a human
found styrene workers had increased mortality or inci-
dences of lymphohematopoietic cancers (leukaemia or carcinogen based on limited evidence of carcinogenicity in
lymphoma or all), with suggestive evidence for pancreatic humans, sufficient evidence of carcinogenicity in experimental
and esophageal tumours. No adequate human studies are animals, and supporting mechanistic data.’
available for styrene-7,8-oxide although this is the primary NTP further affirms, regarding human studies (1), that: ‘The
and active epoxide metabolite of styrene. Both are limited evidence for the carcinogenicity of styrene in humans
genotoxic and form DNA adducts in humans. is based on studies of workers exposed to styrene that showed
(1) increased mortality from or incidence of cancer of the
lymphohematopoietic system and (2) increased levels of DNA
adducts and genetic damage in lymphocytes from exposed
workers. Elevated risks of lymphohematopoietic cancer were
Commentary found among workers with higher exposure to styrene after an
Styrene (vinyl benzene) is an economically important industrial appropriate elapsed time since first exposure. In some studies, the
chemical used in the synthesis and manufacture of polystyrene and risks increased with increasing measures of exposure, such as
hundreds of different copolymers, as well as numerous other average exposure, cumulative exposure, or number of years since
industrial resins. Roughly 99% of the industrial resins produced first exposure. However, the types of lymphohematopoietic cancer
from styrene can be grouped into six major categories: polystyrene observed in excess varied across different cohort studies, and
(50%), styrene-butadiene rubber (15%), unsaturated polyester excess risks were not found in all cohorts. There is also some
resins (glass reinforced) (12%), styrene-butadiene latexes (11%), evidence for increased risks of esophageal and pancreatic cancer
acrylonitrile-butadiene-styrene (10%) and styrene-acrylonitrile among styrene-exposed workers. Causality is not established,
(1%) (1). The 2006 US production of styrene was 11.4 million as the possibility that the results were due to chance or to
pounds (1), produced principally by catalytic dehydrogenation of confounding by exposure to other carcinogenic chemicals cannot
ethylbenzene. be completely ruled out. However, a causal relationship between
Among others before, Teixeira et al. (2) recently reported styrene exposure and cancer in humans is credible and is supported
cytogenetic and DNA damage in workers exposed to styrene and by the finding of DNA adducts and chromosomal aberrations in
concluded their findings were supported by previous study results lymphocytes from styrene-exposed workers.’
demonstrating genotoxicity associated with occupational expo- The NTP conclusion that styrene is ‘reasonably anticipated to
sure to styrene (e.g. 3). Government Agency reviews also be a human carcinogen’ based on induced cancers, genotoxicity
concluded that styrene and its major metabolite styrene-7,8-oxide and mechanism is further bolstered by the 2010 case–control
(SO) are both mutagenic and clastogenic as well as carcinogenic study in six European countries by Cocco et al. (8) who reported
(1,4). The authors (2) quote correctly that the ‘International significantly elevated risks for B-cell non-Hodgkin’s lymphoma
Agency for Research on Cancer (IARC) classified styrene as [odds ratio (OR) 5 1.6; 95% confidence interval (CI) 5 1.1–2.3]
possibly carcinogenic to humans (Group 2B) and SO as probably and for follicular lymphoma (OR 5 2.6; 95% CI 5 1.3–5.2) in
carcinogenic to humans (Group 2A)’. IARC’s (5) evaluation of the relation to styrene exposure. Exposure-related trend analyses
available human studies nearly 10 years ago stated ‘There is also demonstrated increased risks (P , 0.05) for lymphomas
limited evidence in humans for the carcinogenicity of styrene’, in relation to increases in styrene exposures. Budroni et al. (9)
Ó The Author 2011. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society.
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J. Huff and P. F. Infante

in 2010 likewise demonstrated significantly elevated risks in 3. Vodicka, P., Koskinen, M., Naccarati, A., Oesch-Bartlomowicz, B.,
petrochemical workers exposed to styrene when data for Vodickova, L., Hemminki, K. and Oesch, F. (2006) Styrene metabolism,
genotoxicity, and potential carcinogenicity. Drug Metab. Rev., 38,
all categories of non-Hodgkin’s lymphoma are combined 805–853.
(Standardized Incidence Ratio 5 1.87, 95% CI 5 1.01–2.99, 4. RoC (2011) Styrene Oxide CAS No. 96-09-3. Reasonably Anticipated to Be
based on 15 cases) (10). These two papers add to the accumulated a Human Carcinogen. 12th Report on Carcinogens, National Toxicology
evidence linking styrene exposure to human cancers. IARC in Program. pp. 391–392. http://ntp.niehs.nih.gov/ntp/roc/twelfth/profiles/
StyreneOxide.pdf (accessed June 17, 2011).
2002, nearly 10 years ago, concluded that the evidence was 5. IARC (2002) Some traditional herbal medicines, some mycotoxins, naphtha-
already considerable but not fully sufficient for causality (5). lene and styrene. IARC Monogr. Eval. Carcinog. Risks Hum., 82, 1–556.
For possible other human cancer sites related to styrene 6. Boffetta, P., Adami, H. O., Cole, P., Trichopoulos, D. and Mandel, J. S.
exposures, NTP asserts ‘Studies in the reinforced-plastics industry (2009) Epidemiologic studies of styrene and cancer: a review of the
provided evidence that suggests a possible association between literature. J. Occup. Environ. Med., 51, 1275–1287.
7. SIRC. (2008) RE: Request for NTP to Fully Consider New Styrene
styrene exposure and cancer of the esophagus or pancreas.’ (1). Epidemiology Review Prior to Finalizing Styrene Draft Substance Profile.
Additionally, increases in cancer ‘at these sites were also observed 16 Dec 2008, 3 page letter to Wilson SH, NIEHS from Synder J, SIRC.
in some of the individual cohort studies, and there was some http://ntp.niehs.nih.gov/files/20081216SIRC.pdf (accessed June 20, 2011).
evidence of an exposure–response relationship with pancreatic 8. Cocco, P., t’Mannetje, A., Fadda, D. et al. (2010) Occupational exposure
to solvents and risk of lymphoma subtypes: results from the Epilymph
cancer’ (1). case-control study. Occup. Environ. Med., 67, 341–347.
Additional evidence for styrene and human cancers is 9. Budroni, M., Sechi, O., Cesaraccio, R. et al. (2010) Cancer incidence among
supported by carcinogenesis bioassays as sufficient evidence petrochemical workers in the Porto Torres industrial area, 1990–2006.
for the carcinogenicity of styrene in experimental animals Med. Lav., 101, 189–198 [Italian].
based on the induction of tumours in multiple studies in mice 10. Infante, P. F. and Huff, J. (2011) Cancer incidence among petrochemical
workers in the Porto Torres industrial area. Med. Lav., 102. in press.
exposed to styrene by two routes of exposure. The most robust 11. Huff, J. (1984) Styrene, styrene oxide, polystyrene, and beta-nitrostyrene/
studies are a 2-year inhalation study in CD-1 mice and a 2-year styrene carcinogenicity in rodents. Prog. Clin. Biol. Res., 141, 227–238.
oral gavage study in B6C3F1 mice, showing significantly 12. Melnick, R. L. (2002) Carcinogenicity and mechanistic insights on the
increased incidences of lung tumours in male and female CD-1 behavior of epoxides and epoxide-forming chemicals. Ann. N. Y. Acad. Sci.,
982, 177–189.
mice, in male B6C3F1 mice and in both sexes of O20 mice 13. Huff, J. (2002) Chemicals studied and evaluated in long-term carcinogen-
(1,11–13). Interestingly, nearly 25 years ago and confirmed 10 esis bioassays by both the Ramazzini Foundation and the National
years ago IARC concluded that there was already evidence for Toxicology Program: in tribute to Cesare Maltoni and David Rall. Ann. N.
the carcinogenicity of styrene in animals (5). These collective Y. Acad. Sci., 982, 208–230.
carcinogenicity findings clearly support, predated and predicted 14. Huff, J. (2010) Predicting chemicals causing cancer in animals as human
carcinogens. Occup. Environ. Med., 67, 720.
styrene carcinogenicity in humans (14–21), as nearly one-third 15. Tomatis, L., Melnick, R. L., Haseman, J., Barrett, J. C. and Huff, J. (2001)
of known human carcinogens were first identified in long-term Alleged misconceptions’ distort perceptions of environmental cancer risks.
bioassays (22–25). FASEB J., 15, 195–203.
Hence, based on both animal and human cancer studies and 16. Tomatis, L. (2006) Role of experimental and epidemiological evidence of
carcinogenicity in the primary prevention of cancer. Ann. Ist Super Sanita,
genotoxic findings including clastogenicity and DNA damage in 42, 113–117.
workers as well as on other supportive and biologically plausible 17. Tomatis, L. (2006) Identification of carcinogenic agents and primary
mechanistic results, styrene and styrene-7,8-oxide should be prevention of cancer. Ann. N. Y. Acad. Sci., 1076, 1–14.
considered as presenting carcinogenic risks to humans, particularly 18. Infante, P. F. (1991) Prevention versus chemophobia: a defence of rodent
for lymphatic/hematopoietic cancers. Moreover, in the interests of carcinogenicity tests. Lancet, 337, 538–540.
19. Huff, J. (1999) Animal and human carcinogens. Environ. Health Perspect.,
public and occupational health, we suggest that authors be more 107, A341–A342.
cautious in their casual acceptance of industry papers and reviews 20. Huff, J. (1999) Long-term chemical carcinogenesis bioassays predict
of epidemiological study results related to occupational exposure to human cancer hazards. Issues, controversies, and uncertainties. Ann. N. Y.
styrene (or other chemicals). Ultimately, more emphasis needs to Acad. Sci., 895, 56–79.
21. Straif, K., Baan, R. and Cogliano, V. (2006) Butadiene or styrene or
be directed towards primary prevention as the most reliable channel butadiene and styrene or else? Occup. Environ. Med., 63, 157–158.
for reducing or eliminating cancer burdens, especially among 22. Tomatis, L. (1979) The predictive value of rodent carcinogenicity tests in the
workers exposed to known carcinogens and mutagens (16,26,27). evaluation of human risks. Annu. Rev. Pharmacol. Toxicol., 19, 511–530.
23. Huff, J. (1993) Chemicals and cancer in humans: first evidence in
experimental animals. Environ. Health Perspect., 100, 201–210.
Funding 24. Tomatis, L., Aitio, A., Wilbourn, J. and Shuker, L. (1989) Human
carcinogens so far identified. Jpn. J. Cancer Res., 80, 795–807.
National Institute of Environmental Health Sciences, National 25. Huff, J. (1994) Chemicals causally associated with cancers in humans and in
Institutes of Health. laboratory animals: a perfect concordance. In Waalkes, M. P. and Ward, J. M.
(eds), Carcinogenesis. Raven Press, New York, NY, USA, Chapter 2, pp. 25–37.
26. Melnick, R. L., Huff, J. (2011) Lorenzo Tomatis and primary prevention
Acknowledgements of environmental cancer. Environ. Health, 10 (Suppl 1), S14. http://www.
ehjournal.net/content/10/S1/S14.
P.F.I. was a member of the NTP RoC Styrene Expert Panel Meeting, July 2008. 27. Huff, J. (2011) Primary prevention of cancer. Science, 332, 916–917.
Conflict of interest statement: None declared.

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