Table 1.
Reported effects for pesticides that target the mammary gland and use of these data in EPA risk evaluations.
| 1a. Flagged for mammary tumors | |||||
|---|---|---|---|---|---|
| Pesticide | Reason included | Summary of mammary effects in RED or review article | Study/EPA conclusion in RED re: mammary effects | Cancer risk assessment summary from EPA OPP or other authoritative sourcea | Comment on EPA risk evaluation |
| Alachlor | Mammary tumors noted in RED (EPA OPPTS, 1998b) | Significantly increased incidence of mammary gland adenofibromas, fibroadenomas, and/or papillary adenocarcinomas combined at the low and high doses relative to control | Doses with significant effects on the mammary gland were considered to be excessively toxic so effects on mammary tumors were not considered treatment related | “Likely” to be a human carcinogen at high doses, but “not likely “at low doses Basis: increased incidence of malignant and combined benign/malignant nasal, stomach, and thyroid tumors in rats | Mammary tumors at highest dose were dismissed in RED based on the dose being “excessively toxic” but the increase at the low dose is not discussed. |
| Ametrynb | Mammary tumors noted in RED (EPA OPPTS, 2005) | Mammary tumors in female rats at high dose (500 ppm) | Dose with significant effect on the mammary gland considered to be excessively toxic so mammary gland tumors not considered treatment related | Classification updated in 2017 (EPA OPP, 2018): suggestive evidence of carcinogenic potential | Mammary tumors at highest dose were dismissed in RED based on the dose being “excessively toxic” |
| Atrazineb | Mammary tumors in RED (EPA OPPTS, 2006a); effects on mammary gland development in review article (Rodgers, 2018) | Mammary gland tumors observed in female rats (RED) Rats exposed in utero to atrazine or its degradates in drinking water experienced delayed mammary gland development that persisted into adulthood (Rodgers, 2018) | Mechanism of tumor formation considered not relevant in humans. The proposed POD for non-cancer effects, based upon attenuation of the LH surge, appears to be protective against adverse reproductive/developmental outcomes such as delays in onset of puberty, disruption of ovarian cyclicity and inhibition of suckling-induced prolactin release. | Not likely to be carcinogenic to humans Basis: cancer mode of action considered not relevant to humans | EPA’s conclusion that the rodent mammary tumors induced by atrazine are not relevant to humans has been generally well-accepted based on atrazine’s induction of persistent estrus in that model. However atrazine’s ability to alter mammary gland development remains a concern because the mechanism may be independent of the attenuated LH surge that is the basis for the POD. This question is not addressed in the atrazine risk assessment (EPA OCSPP, 2018). EPA also notes a study that did not find altered mammary gland development from atrazine. |
| Captafol | Mammary tumors noted in review article (Rudel, 2007) | Increased incidence of tumors in mammary gland of rats | EPA RED not available. EPA reports mammary and other tumors in rats and lymphosarcomas in mice (EPA OPPTS, 1987). | Probable human carcinogen (Group B) Basis: lymphosarcoma in mice (EPA OPPTS, 1987). | Mammary tumors in rats are considered in the EPA 1987 cancer risk assessment (EPA OPPTS, 1987) |
| Chlordane | Mammary tumors noted in review article (Rudel, 2007) | Limited evidence of mammary gland tumors (Rudel, 2007). | EPA RED not available. EPA IRIS document does not mention mammary tumors. | EPA IRIS classified chlordane as a probable human carcinogen (B2) Basis: human epidemiology studies showing non-Hodgkin’s lymphoma, liver tumors in mice, liver toxicity, and structural similarity to other rodent liver carcinogens (EPA IRIS, 1998). | Mammary tumors are not considered in EPA cancer risk assessment |
| Clonitralid (Niclosamide) | Mammary tumors noted in review article (Rudel, 2007) | Increased mammary adenocarcinomas in male and female rats - findings considered equivocal based on life-table analysis | Since this is not a food use pesticide, carcinogenicity evaluation was not required (EPA OPPTS, 1999a). A 1978 NCI cancer study in rats and mice concluded there was no convincing evidence of carcinogenicity but did note elevated mammary tumors with dose-response compared with historical controls (NCI, 1978). | Mammary tumors dismissed in risk evaluation because of higher than usual incidence in controls. | |
| 1,2-dibromo-3-chloropropane (DBCP) | Mammary tumors noted in review article (Rudel, 2007) | Induced carcinomas in mammary gland of female rats following administration by gavage | No RED, but in a chemical summary published in 2000 EPA notes that high incidences of tumors of the nasal tract, tongue, adrenal cortex, and lungs of rodents were reported in a National Toxicology Program (NTP) inhalation study, and that a gavage study showed tumors of forestomach and mammary gland (EPA, 2000a) | NTP RoC classified as reasonably anticipated to be a human carcinogen Basis: sufficient evidence of carcinogenicity from studies in experimental animals. When administered by stomach tube caused cancer of the forestomach (squamous-cell carcinoma) in rats and mice of both sexes and mammary-gland cancer (carcinoma) in female rats (NTP, 2016a). | Mammary tumors from gavage study are acknowledged. Emphasis is on inhalation study, which reported other tumors. |
| Dichlorvos (DDVP) | Mammary tumors noted in RED (EPA OPPTS, 2006d) and review article (Rudel, 2007) | Increased incidence of mammary gland fibroadenoma in female rats at administered dosages; one female rat with fibroma (EPA OPPTS, 2006d). Increased incidence of mammary gland fibroadenomas/adenomas in a group of female rats upon oral administration (Rudel, 2007) | No additional discussion of mammary tumors | Suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic potential. Basis: increased incidence of forestomach tumors in mice and mononuclear cell leukemia (MCL) in rats |
Mammary tumors are described in RED with no additional discussion |
| Dichloropropene (1,3-D)/Telone | Mammary tumors noted in RED (EPA OPPTS, 1998a) | Increased tumors (including mammary) in both sexes of rats and mice. An impurity of 1,3-D (1,2-D) was shown to have a dose-related trend in mammary adenocarcinomas in female rats | Classified as a probable human carcinogen. | Probable human carcinogen (B2) Basis: increased tumors in both sexes of rats and mice including tumors of the forestomach, liver, mammary, thyroid, adrenal, urinary, and lung. | Mammary effects mentioned in RED and considered in carcinogen risk assessment. This chemical is genotoxic. Many other epoxide-forming chemicals also cause mammary tumors. |
| Difenzoquat | Mammary tumors noted in RED (EPA OPPTS, 1994a) | Neoplastic lesions observed in the mammary glands of female rats including adenocarcinomas and fibroadenomas | Neoplastic lesions in mammary glands considered not treatment related | Evidence of non-carcinogenicity for humans Basis: lack of evidence in adequate studies with rats and mice |
Mammary tumors were dismissed in RED as not treatment related. Tumors observed in the following tissues were also dismissed as not treatment related: adrenals (cortical adenoma), lungs (reticulum cell sarcoma), pituitary (adenoma), ovaries (adenoma) and uterus (polyps). Thyroid follicular adenocarcinoma in the mid-dose and high-dose male rats was determined to be below historical controls. Ultimately EPA concluded that none of the neoplasms were treatment-related. |
| Diuron | Mammary tumors noted in RED (EPA OPPTS, 2003a) | Increased incidence of mammary gland carcinomas in female mice at doses exceeding 600 mg/kg/day | Classified as a “known/likely” human carcinogen | Known/likely mammary carcinogen Basis: urinary bladder carcinomas rats, kidney carcinomas in male rats, and mammary gland carcinomas in female mice | Mammary tumors noted in RED and considered in carcinogen risk assessment |
| Ethalfluralin (Trifluralin) | Mammary tumors noted in RED (EPA OPPTS, 1995a) | Mammary gland fibroadenomas and adenomas/fibroadenomas combined in female rats at mid and high doses | Classified as a possible human carcinogen | Possible human carcinogen (C) Basis: increased mammary gland fibroadenomas and adenomas/fibroadenomas combined in female rats | Mammary tumors noted in RED and considered in carcinogen risk assessment |
| Etridiazole (Terrazole) | Mammary tumors noted in RED (EPA OPPTS, 2000) | Increased incidence of mammary tumors in rats | Classified as a probable human carcinogen | Probable human carcinogen (B2) Basis: increased incidence of multiple tumors types in rats, including the liver, bile duct, mammary gland, thyroid and testes | Mammary tumors noted in RED and considered in carcinogen risk assessment. Positive for mutagenicity. |
| Fenvalerate (Pydrin) | Mammary tumors noted in review article (Parker et al., 1984 in Rudel, 2007) | Significantly increased incidence of benign mammary tumors in female rats upon oral administration | EPA RED not available. Authors of study concluded effects were not treatment related because effects were within historical control range (Parker et al., 1984) | EPA 1996 classified as Group E — Evidence of non-carcinogenicity for humans based on studies in rats and mice; mammary tumors are not mentioned in this document although Parker (1984) was reviewed (EPA OPP, 1996) | Parker et al., (1984) dismissed mammary tumors and mammary tumors are not discussed in the EPA 1996 risk evaluation (EPA OPP, 1996). |
| Folpet | Mammary tumors noted in RED (EPA OPPTS, 1999b). | Increased incidence of mammary benign fibroepithelial tumors observed in female rats at the highest dose compared to control | No additional discussion | Classification updated in 2010 (EPA OPP, 2018): not likely to be carcinogenic to humans at doses that do not cause an irritation response in the mucosal epithelium | Mammary and thyroid C-cell adenomas noted at high dose in RED with no additional comment about carcinogenicity. NOAEL set below doses where tumors were observed. |
| 3-Iodo-2-propynyl butylcarbamate (IPBC) | Mammary tumors noted in RED (EPA OPPTS, 1997a) | Incidence of mammary gland fibroadenoma and combined fibroadenoma/carcinoma significantly increased at the lowest dose relative to control by pairwise comparison. Mid-dose not reported and high dose reported as similar to controls. Body weight reduced at high dose. | Except for the lowest dose (20 mg/kg/day), incidence of tumor was within historical control range and because incidence at the highest dose tested (80 mg/kg/day) was almost equal to control incidence of mammary fibrodenomas declared unrelated to treatment | Not likely to be carcinogenic in humans Basis: lack of evidence in carcinogenicity studies | Mammary tumors at low dose dismissed in RED because of lack of a dose-relationship. Lower mammary tumor incidence at higher doses may be due to body weight decreases, which are known to reduce mammary tumors (Haseman et al., 1997). |
| Malathion | Mammary tumors and developmental effects noted in review article (Rodgers, 2018) No mention of mammary effects in RED (EPA OPPTS, 2009) | Rats in late puberty exposed to levels high enough to inhibit AcE had increased TEB formation and mammary tumors (Cabello et al., 2001). Another study in rats found that alone and combined with E2, malathion altered mammary gland structure and induced mammary tumors (Calaf and Echiburú-Chau, 2012). These were not regulatory toxicology studies. | EPA in 2009 RED describes malathion carcinogenicity as “suggestive” and mammary tumors are not mentioned. RED also notes the CARC review of Cabello et al. (2001) – which reports mammary effects and tumors—concluded that the paper provided insufficient basis for revising the cancer classification for malathion, however this CARC report is not currently public. EPA RED also notes that the risk assessment is considered protective of any potential carcinogenic effects. | Suggestive evidence of carcinogenicity but not sufficient to assess human carcinogenic potential. Basis: Liver tumors in rats and mice at excessive doses as well as rare tumors (nasal) that cannot be distinguished as treatment induced or random occurrence Note that 2000 CARC assessment concluded malathion is a likely human carcinogen based on liver and nasal tumors (CARC, 2000) | Mammary tumors and effects on mammary gland development reported in two studies were summarized in the Rodgers (2018) review. Also, the 2000 EPA CARC assessment reports mammary gland tumors in 2-year rat studies (as well as liver, adrenal, thyroid, uterine) but doesn’t discuss mammary tumors any further and dismisses most of the others, retaining a concern about liver and nasal tumors. Effects on mammary gland development are not discussed in the 2009 RED, except for a note that by protecting for AChE inhibition they protect for effects reported in Cabello et al. (2001). |
| Oryzalin | Mammary tumors noted in RED (EPA OPPTS, 1994c) | Increased incidence of mammary gland tumors in female rats at 300 ppm. | Classified as a possible human carcinogen based on mammary, skin, and thyroid tumors. | Classification updated in 2003 (EPA OPP, 2018): Likely human carcinogen | Mammary tumors noted in RED and considered in carcinogen risk assessment. |
| Parathion (parathion-ethyl) | Mammary tumors and developmental effects noted in review article (Rodgers, 2018) | Rats in late puberty exposed to levels high enough to inhibit AcE had increased TEB formation and mammary tumors (Cabello, 2001). | No RED | Limited data on carcinogenicity in animals available; increased adrenal cortical tumors and benign pancreatic tumors were observed in rats orally exposed to parathion. EPA has classified parathion as a Group C, possible human carcinogen. EPA notes that cholinesterase inhibition is caused by doses far below those eliciting carcinogenic effects (EPA OPP, 2000). | Mammary tumors were reported in 2001, and so are not discussed in cancer risk assessment conducted in 1989 (EPA OPPTS, 1989) Non-cancer risk discussion is focused on acute toxicity from cholinesterase inhibition. |
| Paraquat dichloride | Mammary tumors noted in RED (EPA OPPTS, 1997b) ( | Frequent lesions observed in various organs in rats including the mammary glands (cysts, adenomas, fibromas, fibroadenomas and adenocarcinomas) | Lesions did not appear to be treatment related (either a dose-relationship was lacking or the incidence was similar in the controls and treated groups) | Evidence of non-carcinogenicity for humans Basis: lack of evidence of carcinogenicity in studies with rats and mice | Mammary tumors were dismissed in RED due to lack of a dose-relationship and/or tumors within control range. |
| Phosmet | Mammary tumors noted in RED (EPA OPPTS, 2006e) | Increased mammary gland tumors in female mice | Classified as having suggestive evidence of carcinogenicity but not sufficient to assess carcinogenicity potential in humans | Suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic potential. Basis: Increased liver carcinomas/adenomas in male mice and mammary gland tumors in female mice but not carcinogenic in rats. CARC suggested using RfD approach as for non-cancer risks. | Mammary tumors mentioned in RED and considered in carcinogen risk assessment. |
| Propazineb | Mammary tumors noted in TRED (EPA OPPTS, 2006b) | Mammary and pituitary tumors noted as well as similarity to atrazine MOA. | Mentions similarity to atrazine for which mechanism of mammary tumor formation not relevant to humans | Cancer risks have not been assessed but considered not likely to be a human carcinogen due to having a mechanism of action similar to atrazine | Mammary and pituitary tumors noted in RED and considered not relevant to humans based on MOA similarity to atrazine. |
| Propylene oxide | |||||
| Mammary tumors noted in RED (EPA OPPTS, 2006f) | Significant incidences of fibroadenomas and tubulopapillary carcinomas in the mammary glands of female rats at the high dose. Multiplicity of fibroadenomas significantly increased at all doses | While incidence at the high dose exceeded the historical control range, higher incidence of mammary tumors were expected because the study went 28 months. So EPA questions whether this evidence supports propylene oxide being a systemic carcinogen. | Probable human carcinogen Basis: forestomach tumors in rat and nasal tumors in mice | Mammary tumors in rats (EPA OPPTS, 2006f) and mice (EPA OPPTS, 1991b) were dismissed in RED despite the fact that PrO is structurally similar to ethylene oxide, which causes mammary gland tumors in rodents and is associated with elevated breast cancer in humans (Rudel, 2014). Also PrO and EtO are epoxide-forming chemicals, a class that is known to induce mammary tumors. | |
| Silicon dioxide (diatomaceous earth) | Mammary tumors noted in RED (EPA OPPTS, 1991a) | Nine incidences of mammary fibroadenomas in rats treated with 20 mg/day diatomaceous earth compared to five instances in controls (significance not given) | No additional comment | IARC expressed opinion that silicon dioxide was not classifiable as to its carcinogenicity in humans | mammary effects mentioned in RED with no additional comment |
| Simazineb | Mammary tumors noted in RED (EPA OPPTS, 2006g) | Mammary and pituitary tumors noted as well as similarity to atrazine MOA. | Mentions similarity to atrazine for which mechanism of mammary tumor formation not relevant to humans | Cancer risks have not been assessed but considered not likely to be a human carcinogen due to having a mechanism of action similar to atrazine | Mammary and pituitary tumors noted in RED and considered not relevant to humans based on MOA similarity to atrazine. |
| Sulfallate | Mammary tumors noted in review article (Rudel, 2007) | Induced mammary adenocarcinomas in female rats and mice after oral (diet) administration | EPA RED and risk assessment not available | NTP RoC classified as reasonably anticipated to be a human carcinogen Basis: sufficient evidence of carcinogenicity from studies in experimental animals: Dietary administration of sulfallate caused cancer of the mammary gland (adenocarcinoma) in female rats and mice, cancer of the forestomach (squamous-cell carcinoma) in male rats, and benign lung tumors (alveolar/bronchiolar adenoma) in male mice (NTP, 2016b) | Mammary tumors are considered in the NTP ROC carcinogenicity assessment (NTP, 2016b) |
| Terbuthylazineb | Mammary tumors noted in RED (EPA OPPTS, 1995b) | Increase in mammary gland carcinomas relative to the control group at the highest dose | Dose with observed mammary effects considered to be that with excessive systemic toxicity (exceeding the MTD) and tumor incidence said to be of “uncertain relevance to humans” | Inadequate evidence to determine carcinogenicity in humans Basis: Mammary and testis tumors only observed at a dose that exceeded the MTD and were only seen in one species, so considered of uncertain relevance to humans. | Mammary tumors dismissed in RED because they were observed only at the highest dose, which was described as an excessively toxic dose. Note decreased BW at all doses which may mask mammary tumor effects from the treatment (Haseman et al., 1997). |
| Triclopyr | Mammary tumors noted in RED (EPA OPPTS, 1998e) | Female mice showed a significant increasing trend in mammary gland adenocarcinomas. Additionally, female rats showed significant increasing trends in mammary gland adenocarcinomas and in adenomas and/or adenocarcinomas combined. Significant pair-wise difference of gland adenomas and/or adenocarcinomas combined at the high dose compared to control. | Increases in mammary tumors considered to be marginal and there was an absence of support from structural analogs or genotoxicity | Not classifiable as to human carcinogenicity Basis: carcinogenicity in animals considered to be marginal (“not entirely negative, but yet not convincing”) | Mammary tumors were dismissed in RED despite being observed in female mice and rats with dose-response trend. Body weight reductions at higher doses may have masked a mammary tumor response (Haseman et al., 1997). |
| 1b. Flagged for other mammary effects | |||||
| Pesticide | Reason included | Summary of mammaryeffects in RED or review m article | Study/EPA conclusion in RED re: ammary effects | Cancer risk assessment summary from EPA OPP or other authoritative sourcea | Comment on EPA risk evaluation |
| Amitrole | Mammary effects mentioned in RED (EPA OPPTS, 1996) | A high incidence and/or severity of acinar and/or ductular epithelial cell vacuolation in the mammary gland at the highest dose | No additional comment; LOEL for reproductive toxicity set to 112.5 ppm and the NOEL to 15 ppm | Probable human carcinogen Basis: thyroid tumors in rats and mice; liver tumors in mice | Mammary effects mentioned in RED as occurring in 2-gen repro study at highest dose. NOEL was set below this dose. |
| Atrazine (see above) | |||||
| Chlorpyrifos | Mammary gland developmental effects are described in review article (Rodgers, 2018) No mention of mammary effects in RED (EPA OPPTS, 2006c) | A study reported altered mammary gland development and circulating hormone levels in adult rats in 2016 | No mention of mammary in 2011 EPA risk evaluation or 2016 EPA Revised Human Health Risk Assessment (EPA OCSPP, 2016) | Group E: Evidence of non-carcinogenicity for humans | No mention of mammary effects in RED. Chlorpyrifos altered mammary gland development and circulating hormone levels at doses below US Environmental Protection Agency’s (EPA) benchmark dose for AChE inhibition, indicating AChE may not be the most sensitive endpoint. Effects on mammary gland development are not captured in 2016 EPA evaluations for chlorpyrifos (summary from Rodgers, 2018). |
| Diphenylamine | Mammary swelling mentioned in RED (EPA OPPTS, 1998c) | Swelling of the mammary glands at the highest dose in female rats | Swelling of mammary gland at 5000 ppm; NOEL set to less than 500 ppm. | Not likely to be carcinogenic to humans Basis: lack of evidence in two acceptable carcinogenicity studies |
Mammary swelling mentioned in RED at high dose with no additional comment, and NOEL set at lower dose. |
| Malathion (see above) | |||||
| Meta-cresol | Mammary atrophy mentioned in RED (EPA OPPTS, 1994b) | Mammary, ovarian, and uterine atrophy observed in female mice at 30,000 ppm | No additional comment; LOEL set to 10,000 ppm and NOEL set to 3000 ppm | EPA IRIS classified as possible human carcinogen Basis: Increased incidence of skin papillomas in mice in an initiation-promotion study. The three cresol isomers produced positive results in genetic toxicity studies both alone and in combination (EPA IRIS, n.d.). | Mammary atrophy mentioned in RED and NOEL set below the dose with this effect. |
| Metribuzin | Mammary pathology noted in RED (EPA OPPTS, 1998d) | Pathological changes in mammary glands at the highest dose. | Acknowledgement of toxicity at the highest dose but overall no evidence of carcinogenicity in either sex; LOEL for chronic toxicity set to 300 ppm and NOEL set to 100 ppm | Not classifiable as to human carcinogenicity Basis: lack of evidence for carcinogenicity | Mammary pathology (not further described) is considered in RED non cancer risk evaluation. |
| Methoxychlor | Effects on mammary gland development noted in review article (Rudel, 2011) | Increased area, branches, TEBs, LBs, increased cell division in epithelium at PND in rats after oral (diet) administration of 800 ppm | EPA revoked methoxychlor registration in 2004 based on EDC activity without completing a full risk assessment. A risk summary sets RfD based on fertility effects. Mammary gland is not mentioned in the document (EPA, 2000b) | Not classifiable as to its carcinogenicity to humans (IARC) Not classifiable as to human carcinogenicity (IRIS) | Mammary gland developmental effects noted in Rudel (2011) review. EPA risk assessment focuses on fertility effects and does not mention mammary gland effects (EPA, 2000b) |
| Oxadiazon | Mammary gland effects noted in RED (EPA OPPTS, 2003b) | Inactivation of mammary glands in female rats resulted in disrupted lactation | LOAEL appears to be based on the impaired lactation effect. EPA also notes inactivation not likely due to endocrine disruption. | Likely to be carcinogenic to humans Basis: increased incidence of hepatocellular adenoma and carcinoma in rats and mice | MG effect (impaired lactation) considered in RED non-cancer risk evaluation. |
| Parathion (see above) | |||||
Blank cells indicate data not available from the sources indicated.
a
Cancer classification and basis gathered from REDs unless stated otherwise.
b
A triazine.