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Night Shiftwork and Breast Cancer Risk — Overall Evidence

15 Nov, 10 | by lelliott

Kolstad et al. claim in a letter: “warnings against long-term night shift work to prevent breast cancer are not evidence based” [1]. However, 24 scientists convened by the International Agency for Research on Cancer have concluded, based on sufficient evidence in experimental animals, limited evidence in humans, and strong bio-mechanistic support, that “shiftwork that involves circadian disruption is probably carcinogenic to humans”, (group 2A) [2]. This 200 pages effort by IARC was most definitely ‘evidence based’.

Kolstad et al. base their conclusion solely on a regression analysis of 9 studies. A major impact to their analysis is a large survey of nurses without any information on shiftwork [3]. Further, two of the included studies provide only information on shiftwork for the last 10 or 15 years, respectively, before diagnosis [4, 5]; it is therefore inappropriate to include these two studies in an attempt to construct a ‘dose response’ over decades of work. Despite these severe limitations, they calculate a pooled odds ratio of 1.02 per year (95% CI: 0.92 to 1.13) by increasing years of shiftwork; this would yield a relative risk of 1.49 for 20 years of shiftwork. Overall, this estimate is similar to results from a meta-analysis (RR = 1.40; 95% CI: 1.19-1.65) based on comparison of day-workers with the most extreme shiftwork exposure category in 8 of the same studies as used by Kolstad [6]. Finally, and perhaps most importantly, lack of statistical significance should not, as done by Kolstad, be interpreted as evidence for no effect, particularly when the point estimate (1.49 for 20 years) is far from 1.0.

About 15-20% of the workforce has shiftwork [2]. Therefore, clarifying of carcinogenicity is very important, and should be based on a profound synthesis of all existing documentation, which is extensive [2], but neglected by Kolstad et al. [1].

Johnni Hansen & Richard G. Stevens

References:

1 Kolstad HA, Erlandsen M, Frost P, et al. Should we warn against night shifts to prevent breast cancer? Occup Environ Med 2010;67 (11):797.

2 International Agency for Research on Cancer. IARC monographs on the evaluation of carcinogenic risks to humans. Painting, firefighting, and shiftwork. Lyon: International Agency for Research on Cancer 2010:563-766.

3 Kjaer TK, Hansen J. Cancer incidence among large cohort of female Danish registered nurses. Scand J Work Environ Health 2009;35 (6):446-53.

4 O’Leary ES, Schoenfeld ER, Stevens RG, et al. Shift work, light at night, and breast
cancer on Long Island, New York. Am J Epidemiol 2006;164 (4):358-66.

5 Davis S, Mirick DK, Stevens RG. Night shift work, light at night, and risk of breast cancer. J Natl Cancer Inst 2001;93 (20):1557-62.

6 Viswanathan AN, Schernhammer ES. Circulating melatonin and the risk of breast and endometrial cancer in women. Cancer Lett 2009;281 (1):1-7.

Long-term carcinogenesis bioassays in animals are poor predictors of cancer risk to humans

27 Sep, 10 | by lelliott

In his letter, Predicting chemicals causing cancer in animals as human carcinogens (Occup Environ Med 2010;67:720), Huff surprisingly finds opportunity to promote long-term carcinogenesis bioassays using animals in response to an editorial by Suarthana et al. (Occup Environ Med 2009;66:713e14), Predicting occupational diseases. In their editorial, Suarthana et al. generalize from the development of diagnostic models to predict sensitisation to occupational allergens. Suarthana et al. mention no animal studies and conclude that “[t]here is now an opportunity to develop prediction models for diverse occupational diseases, especially given the existing large epidemiological studies (emphasis added).”

In particular, Huff asserts that “findings from independently conducted bioassays on the same chemicals are consistent, albeit sometimes with additional or different target sites[.]” In fact, a comparison of 121 bioassays from the U.S. National Toxicology Program (NTP) database with those in the published scientific literature found that the studies produced consistent results only 57 percent of the time [1].

Huff also claims that “less than10% of all chemicals if evaluated in bioassays would be predicted to be carcinogenic.” In our analysis of more than 500 NTP bioassays, we show that 259 of the substances evaluated produced evidence of carcinogenicity in at least one group of animals. However, only 89 of these were subsequently classified as known or probable human carcinogens by NTP itself [2]. Even fewer, 40 and 16 respectively, were so classified by the U.S. Environmental Protection Agency and the International Agency for Research on Cancer. This high false positive rate is thought to be largely an indirect effect of increased cell proliferation in response to cell injury and death caused by the near toxic doses of test substances used in the bioassay [3]. Huff also observes that there are more similarities than differences between rodents and humans. However, species-specific modes of action operating in rats or mice but not in humans, including those mediated by α2μ-globulin, peroxisomes, and thyroid-stimulating hormone, also contribute to the high rate of false positives [4].

We must also stress the suffering that animals endure in the bioassay. Not only must they live in the barren, stressful conditions of the laboratory – often including daily forced feeding or forced inhalation – but many will also suffer from exposure to near toxic doses of test substances. This exposure is normally expected to produce lethargy, anemia, diarrhea, weight loss, and other symptoms of sickness and distress.

According to NTP’s own estimates, each bioassay requires killing 860 animals, $2-4 million and five years to plan, conduct, and evaluate. As a result, NTP has conducted an average of only 12 bioassays per year over the past several decades. Considering that humans are potentially exposed to as many as 80,000 environmental chemicals, more than 32 thousand years, 68 million animals, and $160 billion would be required to test them all at this rate.

The time has clearly come for antiquated animal tests like the bioassay to be abandoned in favor of modern, human-relevant methods such as the epidemiological studies recommended in Suarthana et al’s editorial, high-throughput in vitro methods, and computational toxicology.

Joseph Manuppello

[1] Gottmann E, Kramer S, Pfahringer B, et al. Data quality in predictive toxicology: reproducibility of rodent carcinogenicity experiments. Environ Health Perspect 2001;109:509-14.

[2] PETA. Wasted money, wasted lives: A layperson’s guide to the problems with rodent cancer studies and the National Toxicology Program. Norfolk, VA: People for the Ethical Treatment of Animals. 2006. http://www.mediapeta.com/peta/pdf/Wasted-money PDF.pdf (accessed 17 Sept 2010).

[3] Gaylor DW. Are tumor incidence rates from chronic bioassays telling us what we need to know about carcinogens? Regul Toxicol Pharmacol 2005;41:128-33.

[4] Cohen SM. Human carcinogenic risk evaluation: an alternative
approach to the two-year rodent bioassay. Toxicol Sci 2004;80:225-9.

Conflict of Interest: The author is employed by People for the Ethical Treatment of Animals.

Occupational exposure to solvents and risk of lymphoma subtypes: results from the Epilymph case-control study

7 Sep, 10 | by lelliott

Re: Cocco et al., Occup Environ Med 2010; 67: 341-347 (Original article)

Considering the temporal association between exposure to benzene and the later development of leukaemia it is questionable if this phenomena is also true for NHL (1). From several independent epidemiologic studies with
consistent findings it can be concluded that 10 to 15 years after exposure to benzene has been stopped, the risk of leukaemia is significantly less or even absent (2,3,4).

Assuming that the underlying mechanism for leukaemia and NHL is the same, it would be important to use the large database of the “Epilymph study” to analyze the temporal pattern between exposure and disease.

The study found increased risks for chronic lymphocytic leukaemia after exposure to toluene and xylene. A benzene exposure was excluded. These statistical associations must be discussed with respect to the genotoxicologic evidence of these aromatic hydro-carbons. Compared to benzene, toluene and xylene have not been proven as human carcinogens. The IARC Working Group concluded in 1999, that there is inadequate evidence in humans for the carcinogenicity of toluene and xylenes (5). Therefore the
associations must be interpreted with caution and do not support causality.

Gerhard Triebig

1. Triebig G. Implications of latency period between benzene exposure and development of leukemia – a synopsis of literature. Chem Biol Interact 2010; 184: 26-29.

2. Hayes RB, Song-Nian Yin, Dosemeci M. Benzene and the dose related incidence of hematologic neoplasm in China. J Natl Cancer Inst 1997; 89: 1065-1071.

3. Finkelstein MM. Leukemia after exposure to benzene: temporal trends and implications for standards. Am J Ind Med 2000; 38: 1-7.

4. Glass DC, Sim MR, Fritschi L, Gray CN, Jolley DJ, Gibbons CG. Letter to the editor. Leukemia risk and relevant benzene exposure period. Am J Ind Med 2002; 42:481-489.

5. IARC Monographs on the evaluation of carcinogenic risks to humans. Re-evaluation of Some Organic Chemicals, Hydrazine and Hydrogen Peroxide. Volume 71, Part two (Toluene) and Part three (Xylene). World Health Organization International Agency for Research on Cancer, 1999.

Chrysotile dimensions

3 Sep, 10 | by lelliott

In our study showing the exposure to chrysotile fibres in a friction materials producing plant through urinalysis for fibres, it was shown that smaller chrysotile fibres were indeed absorbed and if shorter than 1-2 µm could also be transported in the urine (1). This property could explain effects also in other sites than respiratory tract.

Exposure can also be demonstrated by an electron microscopic analysis for fibres in the nasal lavage liquid. Thus we were able to show individual exposure to refractory ceramic fibres, the nature of which could be ascertained by X-ray diffraction technique in the same samples (2).

Thus, it seems that exposure to, and absorption of, fibres harmful to health can be determined at an individual level. Cohorts thus constituted could prove the ideas presented in this excellent paper (3).

Heikki Savolainen

1. Savolainen H, Cosca-Sliney R, Guillemin M. Detection of
occupational exposure to inorganic fibres by urinary fibre analysis. Occup Hyg 1996; 3: 351-357.

2. Linnainmaa M, Kangas J, Makinen M, et al. Exposure to refractory
cermaic fibres in the metal industry. Ann Occup Hyg 2007; 51: 509-516.

3. Loomis D, Dement J, Richardson D, et al. Asbestos fibre dimensions
and lung cancer mortality among workers exposed to chrysotile. Occup
Environ Med 2010; 67: 580-584.

Mining Disasters

27 Aug, 10 | by lelliott

“Basic protections are still lacking” (Occup Environ Med 2010;67:361) cited several coal-mining tragedies earlier this year and addressed the concern that millions of workers worldwide continue to work under weak standards and lax enforcement. This year, China has reported over 60 mining accidents from explosions, fires, carbon monoxide poisoning, flooding, and cave-ins (China Mine Disaster Watch http://www.usmra.com/chinatable.htm). Many of the accidents occurred in illegal mines and in mines violating safety regulations.

Mine disasters in developed countries are no longer common; however, earlier this year 29 workers were killed in an explosion at a coalmine in West Virginia. This has been described as the worst mine disaster in the United States for the past four decades.

Currently, miners are trapped 2000 feet beneath the earth’s surface from a collapse of the San José Mine in Chile. All miners survived the collapse, but they remain trapped with little hope of rescue for the next three months.

Mr. Sebastián Piñera, the President of Chile, has fired high-ranking mining regulators and ordered a review of worker safety in Chile. Mining unions and employees describe the mine as having a history of violating safety regulations, including the lack of an escape route. (http://www.nytimes.com/2010/08/25/world/americas/25chile.html?pagewanted=1&th&emc=th)

Other countries have experienced mine disasters this year as well. Most of these disasters have cited either violations of safety regulations or lack of safety features altogether.

Announcing the OEM Blog

10 Jun, 10 | by Dana Loomis

By Dana Loomis

I’m pleased to announce the initiation of the Occupational & Environmental Medicine blog, available at http://blogs.bmj.com/oem/. The OEM blog is edited by Dr. Leslie Elliott.  It’s our hope that the blog will serve the occupational and environmental health community as a forum for discussion and debate of current issues in the field. We welcome a wide range of relevant contributions, including comments on articles published in the Journal, discussion of developments of interest to researchers and practitioners, novel observations and ideas for research, news, and announcements.  As this is a new medium for OEM, we expect that the blog will develop in its own way as the community begins to use it.

Blog Policy:

Contributions to the OEM blog are not peer reviewed, but are screened for relevance and appropriateness and may be edited before posting.  As with other correspondence with the Journal, we reserve the right to decline contributions that are trivial, incomprehensible, or represent advertising, and we cannot publish material that is offensive, libelous or illegal.

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