Environment and Breast Cancer: Science Review
We assigned each chemical into one of the following groups based on its major sources and uses: industrial chemicals, chlorinated solvents, products of combustion, pesticides, dyes, radiation and drinking water disinfection, pharmaceuticals, hormones, natural products, and research chemicals.Chlorinated solvent
Found in consumer products
"Likely" indicates that the chemical is contained in consumer products or traces of the chemical are present in products, including food and water, resulting in likely exposure for the general population. For some chemicals marked as "likely," consumer product uses have been discontinued, and this will be indicated in the "Use in Consumer Products" field.Likely
Food additive in US
Chemicals are classified as "Listed" or "Not listed" in the Everything Added to Food in the United States database developed by the US Food and Drug Administration.(22)Listed
California Proposition 65
Chemicals are labeled "Listed" or "Not listed" based on the Proposition 65 list of chemicals updated on May 27, 2005. Listed chemicals are "chemicals known by the State of California to cause cancer or reproductive toxicity"(19).Listed
Chemicals classified as "Likely" air pollutants are those likely to be found in indoor or outdoor air, including products of combustion and industrial chemicals that may offgas from consumer products, leading to human exposure.Likely
Current High Production Volume chemical
Chemicals are classified "Yes" or "No," based on 2002 production volume information submitted to the US EPA: "Yes" for >1 million pounds produced; "No" for < 1 million pounds produced. Some past production volumes are referenced, where appropriate, in the HPV comment column (20). In addition, Scorecard.org is referenced and noted in the HPV comment column when it was inconsistent with current production volume information obtained from US EPA (21).Yes
Production volume information
Production volume information is from the US EPA database on non-confidential production volume information submitted by companies for chemicals under the 1986-2002 Inventory Update Rule (IUR) using the most updated (2002) values (20). The Inventory Update Rule requires the submission of basic production data every four years on chemical substances manufactured (including imported) for commercial purposes in amounts of 25,000 pounds or more at a single site. Out of over 80,000 chemicals on the TSCA Chemical Substances Inventory, reports are required for approximately 9,000 substances. For those substances with annual volumes of 300,000 lbs or more per site, reporters also submit chemical processing and use information.>100 - 500 million
General population exposure
This field includes information describing pathways of exposure for the general population obtained from a variety of sources including: IARC Monographs (9), NTP 11th ROC on Carcinogens (4), NTP Study Reports and Abstracts (3), Hazardous Substance Database (10), and other sources located through use of the Google search engine.Widespread exposure occurs during the production and industrial use of dichloromethane and during the use of a variety of consumer products containing dichloromethane. Substantial losses to the environment lead to ubiquitous low-level exposures from ambient air and water (IARC 1999 vol.:71 p.251). Hazardous air pollutant - measured concentrations: 0.07 to 0.29 µg/m3 in rural areas; < 2 µg/m3 in suburban areas; < 15 µg/m3 in urban areas. Indoor air pollutant due to use in consumer products. Groundwater contaminant (11th ROC).
Use in consumer products
Summaries of chemical use in consumer products were developed from information found in US EPA SRD (11), NLM HPD (12), and Scorecard (12). Major uses were taken from IARC Monographs (9), NTP 11th ROC (4), NTP Study Reports (3), HSDB (10), and PAN Pesticides Database (13). If a chemical could not be found in these sources, we searched ToxNet (14), PubChem (15), and The Merck Index (16), and conducted searches by both name and CAS No. using Google.988 consumer products listed with EPA contain chemical including: fabric cleaners, furniture polish, strippers, auto products, wood sealant and stains, spray paints, aerosols, adhesives, glues, art supplies, insecticides, hair spray propellents-until 1989 (SRD). According to the EPA Consumer Use and Shelf Survey, dichloromethane is used in spray shoe polish, water repellent/protectors, spot removers, wood floor and panel cleaners, contact cement, super glues, spray adhesives, adhesive removers (general purpose, tile and wallpaper), silicone lubricants (excluding automotive), specialized electronic cleaners (for TV, VCR, razor, etc.), wood stains, varnishes and finishes, paint thinners, paint removers, aerosol spray paints, primers, aerosol rust removers, outdoor water repellents, glass frosting/artificial snow, spray lubricant for cars, transmission cleaners, battery terminal protector, brake quieter/cleaner, and gasket removers (11th ROC). Used principally as a solvent, in paint removers, degreasers, aerosol products, and triacetate solutions, and in the manufacture of foam polymers (IARC 1999 vol.:71 p.251). It is also used as a blowing agent in flexible urethane foams, as a process solvent in the manufacture of steroids, antibiotics, vitamins, and tablet coatings, and as an extraction solvent for spice oleoresins, hops, and caffeine from coffee (NTP Report No.306 1986). Not currently registered as a pesticide in US (PAN Pesticides Database).
Occupational exposure to women
We extracted the total number of potentially exposed workers and the number of potentially exposed female workers from the National Occupational Exposure Survey (NOES) 1981-1983; we listed specific industry classifications if >5,000 women were potentially exposed in that industry. Note: NOES does not include farm workers.NOES 1981-1983-Total exposed: 1,438,196; Total female exposed: 352,536; Occupational fields exposed: nurses, lab technicians, maids, electronic equipment assemblers, machine operators-various industries, assemblers, packagers, cosmetologists until 1989 (54 FR 27342, June 29, 1989).
US EPA cancer classification
The US EPA Weight of Evidence Characterization of the chemical’s carcinogenic potential is listed: Group A: Carcinogenic to humans; Group B: Probably carcinogenic to humans. Group C: Possibly carcinogenic to humans. Group D: Not classifiable as to human carcinogenicity. Group E: Evidence of non-carcinogenicity for humans. NA: Not evaluated by US EPA (17).B2: Probably Carcinogenic to Humans, inadequate evidence
US EPA Weight of Evidence narrative
US EPA narrative statement of overall weight of evidence for carcinogenicity (animal, human, and other supportive data).Based on inadequate human data and sufficient evidence of carcinogenicity in animals; increased incidence of hepatocellular neoplasms and alveolar/bronchiolar neoplasms in male and female mice, and increased incidence of benign mammary tumors in both sexes of rats, salivary gland sarcomas in male rats and leukemia in female rats. This classification is supported by some positive genotoxicity data, although results in mammalian systems are generally negative.
US EPA slope factor basis
Lists target organs used for estimating carcinogenic potency of the chemical (17).Oral: Hepatocellular adenomas or carcinomas (NTP) and hepatocellular cancer and neoplastic nodules (NCA)-female/male mouse; Inhalation: Combined adenomas and carcinomas-female mouse
NIOSH Pocket Guide - potential carcinogen?
This field indicates whether NIOSH identifies the chemical as a potential carcinogen for workers (yes/no) (24).yes
OSHA-Is medical surveillance required?
This field indicates whether medical surveillance is required for exposed workers and whether required surveillance includes breast exams or mammography (25).yes, but no mammography
NIOSH Pocket Guide - cancer sites
Lists target organs from animal cancer bioassays (24).lung, liver, salivary gland, mammary gland
Risk assessment summary
For 11 chemicals that are of particular interest because of recent regulatory attention, a Silent Spring Institute summary of how the evidence on mammary gland tumors and the potential for breast cancer was considered in major governmental risk assessments and regulations is available.US EPA and Canadian regulatory agencies have focused on mouse liver and lung tumors to estimate the carcinogenic potency of methylene chloride (1), with little discussion of rat mammary gland tumors except in the US OSHA 1997 regulation (2) lowering exposure levels for workers. Industry groups have argued that mouse tumors are not relevent to humans, and also that the rat mammary gland tumors are not relevent to humans because they are related to prolactin secretion; and the Netherlands and IPCS have adopted these arguments in their risk assessments despite the fact that only limited data support this hypothesis (3,4). In fact, a recent article shows that prolactin plays a major role in human breast cancer and that prolactin-mediated mammary carcinogenesis in rodents is likely to be relevent to humans (5). US OSHA proposed mammography for exposed women as part of required medical surveillance, but this breast cancer screening was dropped from the final regulation following objections from Eli Lilly and others (6).
Other governmental risk assessment documents
For 11 chemicals that are of particular interest because of recent regulatory attention, we identified and summarized risk assessment materials developed by a wide range of agencies and groups. We specifically searched for documents by the following organizations: California EPA Office of Health Hazard Assessment, Health Canada, IARC, International Program on Chemical Safety (IPCS), World Health Organization, RIVM (Dutch chemical standards agency), Toxicology Excellence for Risk Assessment ITER database and Peer Consultation documents, and by searching PubMed, ToxLine, the National Library of Medicine, and Google for documents related to “risk assessment” and the CAS No. or chemical name.US and Canadian regulatory agencies have focused on mouse liver and lung tumors to estimate the carcinogenic potency of methylene chloride (1). While they have considered methylene chloride a probable human carcinogen, the Netherlands and the International Program on Chemical Safety have concluded that methylene chloride is unlikely to be carcinogenic to humans because the evidence from mice is not relevent to humans, or the carcinogenicity is secondary to toxicity (7). The Halogenated Solvents Industry Alliance, Zeneca, and others have argued that mouse liver and lung tumors are not relevent to humans because of species differences in localization of enzymes that activiate the chemical to its reactive intermediate (e.g. 8), and Canadian governmental scientists have argued that the evidence to support this was not convincing (9). In reference to the mammary gland tumors, the IPCS assessment says "Increased incidence of benign mammary tumours in female rats was observed in one study, and increased incidence and multiplicity were observed in two other rat studies. The increased incidence of these tumours was within the historical control range; nevertheless there was a dose-response relationship within one study. It is considered that an increase in a tumour type, which occurs with high and variable incidences in control animals, which does not progress to malignancy, and which may be related to changes in prolactin levels, is of little importance in human hazard assessment" (4). We were unable to locate experimental evidence that fully supports the lack of relevence of methylene chloride-induced mammary gland tumors in rats to humans, and a more recent article shows that "prolactin has a major role in human breast cancer and the similarity of mechanism with the rodent suggests that prolactin-mediated mammary carcinogenesis could be of much higher toxicological relevance to humans than previously thought" (5). US OSHA (2) reduced workplace exposures based on a risk assessment that included consideration of rat mammary gland tumors as well as mouse liver and lung tumors, and OSHA proposed mammography for exposed women as part of required medical surveillance. The proposed breast cancer screening was dropped from the final regulation following objections from Eli Lilly and others (6,10). In its comments, Eli Lilly stated that "General medical literature has well documented that routine medical screens of otherwise healthy, asymptomatic individuals are not useful in leading to early detection and have little impact on long term mortality or morbidity for many commonly identified cancers."
Non-governmental risk assessment documents
For 11 chemicals that are of particular interest because of recent regulatory attention, we identified and summarized risk assessment materials developed by a wide range of agencies and groups. We specifically searched for documents by the following organizations: California EPA Office of Health Hazard Assessment, Health Canada, IARC, International Program on Chemical Safety (IPCS), World Health Organization, RIVM (Dutch chemical standards agency), Toxicology Excellence for Risk Assessment ITER database and Peer Consultation documents, and by searching PubMed, ToxLine, the National Library of Medicine, and Google for documents related to “risk assessment” and the CAS No. or chemical name.Zeneca, the Halogenated Solvents Industry Alliance, and others have argued that the mouse liver and lung tumors are not relevent to humans (8,11).
(1) - US EPA. IRIS Database for Risk Assessment. 2005. - Link
(2) - Occupational Safety and Health Administration. Occupational Exposure to Methylene Chloride. 29 CFR 1910, 1915, and 1926: Federal Register Vol 62, No. 7, 1997. - Link
(3) - RIVM. Re-evaluation of human toxicological maximum permissible risk levels. RIVM, Bilthoven, the Netherlands, 2001. - Link
(4) - International Program on Chemical Safety. Environmental Health Criteria 164: Methylene Chloride (second edition). World Health Organization, 1996. - Link
(5) - Harvey PW. Human relevance of rodent prolactin-induced non-genotoxic mammary carcinogenesis: prolactin involvement in human breast cancer and significance for toxicology risk assessments. J Appl Toxicol 2005;25(3):179-83. - Link
(6) - Eli Lilly and Company. Comments of Eli Lilly and Company on OSHA Proposed Rule for Occupational Exposure to Methylene Chloride, 56 Fed Reg 57036, Docket no. H-71. Lilly Corporate Center, Indianapolis, Indiana, 1992. - Link
(7) - International Program on Chemical Safety. IPCS Workshop on Issues in Cancer Risk Assessment. Fraunhofer Institute of Toxicology and Aeresol Research, Hanover, Germany, 1998. - Link
(8) - Green T. Methylene chloride induced mouse liver and lung tumours: an overview of the role of mechanistic studies in human safety assessment. Hum Exp Toxicol 1997;16(1):3-13. - Link
(9) - Liteplo RG, Long GW, Meek ME. Relevance of carcinogenicity bioassays in mice in assessing potential health risks associated with exposure to methylene chloride. Hum Exp Toxicol 1998;17(2):84-7. - Link
(10) - Motor Vehicle Manufacturers Association. Comments on the OSHA Proposed Rule on Occupational Exposure to Methylene Chloride, 56FR57036. Detroit, MI, 1992. - Link
(11) - Toxicology Excellence for Risk Assessment, ITER Peer Review on Dichloromethane, Cadmium, & Perchlorate Meeting Summary, 1997. - Link