A Systematic Review of Carcinogenic Outcomes and Potential Mechanisms from Exposure to 2,4-D and MCPA in the Environment

Table 1

Summary of reviews of 2,4-D and/or MCPA.

Reference	Evaluation	Conclusions
Regulatory reviews or reviews in support of regulatory activities
US EPA, SAB [27]	Science Advisory Board consultation on carcinogenicity of 2,4-D	“Data are not sufficient to conclude that there is a cause and effect relationship between exposure to 2,4-D and non-Hodgkin’s lymphoma.”
US EPA [28]	4th carcinogenicity of 2,4-D peer review	Not classifiable as to carcinogenicity.
WHO/IARC [29]	Evaluations of carcinogenic risk	Inadequate and/or limited for 2,4-D specifically and chlorophenoxy compounds generally.
US EPA [5]	Health Effects Division Carcinogenicity Peer Review Committee (2,4-D)	“Evidence is inadequate and cannot be interpreted as showing either the presence or absence of a carcinogenic effect.”
European Commission [30]	Review report for 2,4-D	Proposed uses have no harmful effects on animal or human health; no evidence of carcinogenicity.
US EPA [3, 4]	Risk assessments and reregistration decision for MCPA	Limited evidence for carcinogenicity.
US EPA [8]	Risk assessments and reregistration decision for 2,4-D	Group D, not classifiable as to carcinogenicity.
Health Canada PMRA [31]	Reregistration decision for 2,4-D	No evidence of carcinogenicity.
Health Canada PMRA [32]	Reregistration decision for MCPA	No evidence of carcinogenicity.
Health Canada [9]	MCPA in drinking water	Not considered a carcinogen.
77FR23135 [33]	Response to NRDC petition to revoke 2,4-D registration	No new evidence that would suggest registration should be revoked.
Nonregulatory reviews
Canadian Centre for Toxicology [34]	Expert panel on carcinogenicity of 2,4-D	No evidence that 2,4-D forms reactive intermediates in the liver or other tissues or forms adducts with DNA. Existing animal and human data are insufficient to support the finding that 2,4-D is a carcinogen; insufficient evidence that existing uses of 2,4-D pose a significant human health risk.
Kelly and Guidotti [35]	Review of literature to advise provincial regulatory body on chlorophenoxy safety, particulary 2,4-D	Evidence for a causal association is strongest for NHL and probably reflects either a weak effect or, possibly, a confounding exposure associated with the use of 2,4-D. Given worst-case assumptions, potency of 2,4-D as a carcinogen is probably weak. Its intrinsic toxicity is less than that of alternative herbicides.
Johnson [36, 36]	13 cohort studies (9 cohorts) in chlorophenoxy manufacturing; 16 cohort studies (12 cohorts) in chlorophenoxy spraying	The weight of evidence does not unequivocally support an association between use of chlorophenoxys and malignant lymphomas/STS; occupational cohort studies have not accumulated sufficient person-years of observation to date, yet see cases of myeloid lymphoma and STS when none are expected.
Ibrahim et al. [37]	Human carcinogenicity of 2,4-D	The toxicological data alone do not provide a strong basis for determination of carcinogenicity of 2,4-D. Suggestive although inconclusive evidence for an association between exposure to 2,4-D and NHL based on epi studies and further study was warranted. Little evidence of an association between 2,4-D and STS or HD, and no evidence of an association between 2,4-D use and any other form of cancer.
Munroe et al. [38]	Comprehensive, integrated review of 2,4-D safety in humans	No evidence for adverse health effects; no mechanistic basis by which 2,4-D could cause cancer.
Morrison et al. [14]	Meta analysis of epidemiological studies involving occupational exposures to chlorophenoxy compounds	Suggestive evidence of an association with NHL; no evidence for an association with STS, HD, or leukemia.
Bond and Rossbacher [39]	Potential carcinogenicity of MCPA, MCPP, 2,4-DP	No evidence for carcinogenicity across all three compounds.
Henschler and Greim [40]	Comprehensive, integrated review to establish “maximale arbeitsplatz konzentration”	Evidence for potential proliferative response; less evidence for genotoxicity.
Gandhi et al. [41]	Potential carcinogenicity of 2,4-D	Some suggestive evidence for an association with NHL but without any plausible mode of action.
Garabrant and Philbert [42]	Comprehensive, integrated review of potential for health effects in humans	No causal association of any form of cancer with 2,4-D exposure. Animal studies of acute, subchronic, and chronic exposure to 2,4-D, its salts, and esters showed an unequivocal lack of systemic toxicity at doses that did not exceed renal clearance mechanisms. No evidence that 2,4-D in any of its forms activated or transformed the immune system in animals at any dose.
Bus and Hammond [43]	Update on data generated by the Industry Task Force II on 2,4-D Research Data	Toxicity responses limited to highest doses; not a carcinogen or genotoxicant, does not cause birth defects; low potential for reproductive toxicity and neurotoxicity.
Van Maele-Fabry et al. [44]	Cohort studies for chlorophenoxy expousures and leukemia	Meta-analysis of 3 cohort studies; statistically significant odds ratio = 1.60, 95% confidence interval = 1.02–2.52; all three underlying studies individually showed non-significant associations.