Chlorophenoxy compounds, particularly 2,4-dichlorophenoxyacetic acid (2,4-D) and 4-chloro-2-methylphenoxy)acetic acid (MCPA), are amongst the most widely used herbicides in the United States for both agricultural and residential applications. Epidemiologic studies suggest that exposure to 2,4-D and MCPA may be associated with increased risk non-Hodgkins lymphoma (NHL), Hodgkin’s disease (HD), leukemia, and soft-tissue sarcoma (STS). Toxicological studies in rodents show no evidence of carcinogenicity, and regulatory agencies worldwide consider chlorophenoxies as not likely to be carcinogenic or unclassifiable as to carcinogenicity. This systematic review assembles the available data to evaluate epidemiologic, toxicological, pharmacokinetic, exposure, and biomonitoring studies with respect to key cellular events noted in disease etiology and how those relate to hypothesized modes of action for these constituents to determine the plausibility of an association between exposure to environmentally relevant concentrations of 2,4-D and MCPA and lymphohematopoietic cancers. The combined evidence does not support a genotoxic mode of action. Although plausible hypotheses for other carcinogenic modes of action exist, a comparison of biomonitoring data to oral equivalent doses calculated from bioassay data shows that environmental exposures are not sufficient to support a causal relationship. Genetic polymorphisms exist that are known to increase the risk of developing NHL. The potential interaction between these polymorphisms and exposures to chlorophenoxy compounds, particularly in occupational settings, is largely unknown. 1. Introduction The chlorophenoxy herbicides MCPA and 2,4-D are registered for a range of agricultural and residential uses focused on control of postemergent broadleaf weeds. Since 2001, 2,4-D has been the most commonly used herbicide in the residential market at 8 to 11 million pounds annually and is the seventh most commonly used herbicide in the agricultural market ranging from 24 to 30 million pounds annually (http://www.epa.gov/pesticides/pestsales/07pestsales/usage2007_2.htm#3_5/). MCPA is used less, falling within the top 25 compounds used residentially and agriculturally, but is a closely related compound. Phenoxy herbicides act by simulating the action of natural hormones to produce uncoordinated plant growth. Their action is selective as they are toxic to dicotyledonous but not monocotyledonous plants. The physical properties of chlorophenoxy compounds can vary greatly according to formulation. For instance, as alkali salts they
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