Environment and Breast Cancer: Science Review

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MX (3-chloro-4-(dichloromethyl)-5-hydroxy-2(5h)-furanone)
CAS RN 77439-76-0

Major use
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.
Drinking water disinfection byproduct
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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.
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)
Not 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).
Air pollutant
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.
Not 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).
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.
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.
General population may be exposed via contaminated drinking water.
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.
No consumer products listed in SRD, HPD, or Scorecard. Disinfection by-product that has been found at nanogram-per-litre levels in drinking water as a result of chlorination or chloramination (IARC 2004 vol.:84 p.441).
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.
Not listed in NOES.
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).
NIOSH Pocket Guide - potential carcinogen?
This field indicates whether NIOSH identifies the chemical as a potential carcinogen for workers (yes/no) (24).
NIOSH Pocket Guide - cancer sites
Lists target organs from animal cancer bioassays (24).
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.
MX is a mutagenic compound formed during disinfection of drinking water. It has been identified as the major contributor to mutagenicity of chlorinated drinking water (1). Many potentially carcinogenic chemicals are formed during the disinfection process, and many studies have been conducted to describe potential risks. Increased risk of breast cancer has been observed in a few epidemiologic studies, but other cancers (e.g. bladder) have been the focus of this work. MX is the only identified disinfection by-product (DBP) that has been shown to increase mammary gland tumors in animal studies, but many DBPs have not yet been chemically identified or tested. Higher levels of DBPs are formed by chlorination of water polluted with sewage and other organic waste, and the most effective method for reducing levels of DBPs is protection of water quality in the source water (2). US EPA does not mention breast cancer or mammary gland tumors in its most recent regulation pertaining to DBPs; this regulatory risk assessment estimates that between 2 and 17% of all bladder cancers in the US are due to DBPs (3).
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 EPA National Primary Drinking Water Regulations: Stage 2 Disinfectants and Disinfection Byproducts Rule does not mention breast or mammary tumors, but does discuss MX as a disinfection byproduct with carcinogenic potential -- thyroid and liver are mentioned specifically (3). The US EPA Stage 2 rule references a quantitative assessment of carcinogenic risks of MX by EPA but we were unable to locate this document. In 2000 California EPA noted mammary gland tumors in animals in its determination that MX is a carcinogen (4). This document also briefly reviews epidemiologic evidence for carcinogenicity of chlorinated drinking water and notes tumors at multiple sites, although breast cancer is not mentioned. They note that the strongest epidemiological evidence is for bladder cancer. Under Prop. 65, California EPA derived a cancer potency factor for MX considering thyroid, liver, mammary, and adrenal gland tumors observed in the animal studies(5). WHO IPCS reviewed risks from disinfectants and disinfectant byproducts - this document includes a thorough review of epidemiologic studies and reports a few studies showing increased breast cancer(2). It also discusses MX and mentions mammary tumors with a question about whether there was a dose-response - tumor frequencies are reported for the Komulainen study for male rats only.
(1) - National Toxicology Program: Department of Health and Human Services. 11th Report on Carcinogens. 2005. - Link

(2) - World Health Organization International Program on Chemical Safety. Environmental Health Criteria # 216 - Disinfectants and Disinfectant By-Products. 2000. - Link

(3) - US Environmental Protection Agency. National Primary Drinking Water Regulations: Stage 2 Disinfectants and Disinfection Byproducts Rule. vol. 40 CFR part 141: Federal Register, 2003. - Link

(4) - California Environmental Protection Agency. Evidence on the Carcinogenicity of MX (3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone). In: Reproductive and Cancer Hazard Assessment Section OoEHHA, ed., 2000. - Link

(5) - California Environmental Protection Agency. No Significant Risk Level (NSRL) for the Proposition 65 Carcinogen MX (3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone). In: Reproductive and Cancer Hazard Assessment Section OoEHHA, ed., 2001. - Link