Biomonitoring Summary

2,4-Dichlorophenoxyacetic Acid

CAS No. 94-75-7

General Information

Widely used throughout the United States, the chlorophenoxy herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) controls broadleaf weeds in residential, agricultural, and aquatic environments. It was first registered with U.S.EPA in 1948. Similar to other chlorophenoxy herbicides, it acts as a plant growth hormone. At low levels, these herbicides can enhance plant growth, but at higher levels are herbicidal. 2,4-D can be applied either as an aqueous salt or as an oil-soluble esters, and is often mixed with other chlorophenoxy acid herbicides (such as dicamba, MCPA, and mecoprop). As much as 62 million pounds of 2,4-D were used in the U.S. in 2001 (U.S.EPA, 2004). It is poorly bound in soils and has a half-life of several days to several weeks. It is rarely detected in ground waters (USGS, 2007). Acid and salt forms are much less toxic to fish and aquatic invertebrates than the ester forms. One of the environmental breakdown products of 2,4-D is 2,4-dichlorphenol (HSDB, 2011).

General population exposure to 2,4-D may occur during residential applications, by direct contact with agricultural and residential areas after applications, and by consuming food or drinking water contaminated with 2,4-D. Recent estimates of chronic intakes of 2,4-D have been below recommended intake limits (U.S.EPA, 2005). 2,4-D is rapidly absorbed via oral and inhalation routes It is not well absorbed through the skin, although dermal exposure may be significant for herbicide manufacturing plant workers exposed to high concentrations of 2,4-D or for prolonged periods. Once absorbed, 2,4-D is eliminated mostly unchanged in the urine with an elimination half-life ranging from 10 to 33 hours (Arnold et al., 1989; Kohli et al., 1974; Sauerhoff et al., 1977).

Human health effects from 2,4-D at low environmental doses or at biomonitored levels from low environmental exposures are unknown. 2,4-D has low acute toxicity. Intentional overdoses and unintentional high dose exposures to chlorophenoxy acid herbicides have resulted in weakness, headache, dizziness, nausea, abdominal pain, myotonia, hypotension, renal and hepatic injury, and delayed neuropathy (Bradberry et al, 2004. The acid and salt forms of 2,4-D are eye irritants. Acute high doses administered to laboratory animals produced ataxia, myotonia, and evidence of histological injury to the kidneys, liver, thyroid, eyes, adrenals and gonads (NTP, 2006; U.S.EPA, 2005). 2,4-D does not have significant reproductive, developmental, or teratogenic effects in chronic rodent studies (IPCS, 1996; U.S.EPA 2005; Charles et al., 2001). Epidemiological studies have reported associations of several types of cancer, such as soft tissue sarcoma and non-Hodgkin's lymphoma, with the exposure to chlorophenoxy herbicides as defoliants or contaminated herbicides. It is unclear whether these associations are related to the chlorophenoxy herbicides, other exposures, or to contaminants in the herbicide formulations (specifically 2,3,7,8-tetrachlorodibenzo-p-dioxin) (Garabrant and Philbert, 2002; IOM, 2003; IPCS, 1996; Pearce and McLean; 2005; U.S.EPA, 2005). 2,4-D was not genotoxic or carcinogenic in animal studies (Garabrant and Philbert, 2002; IPCS, 1996; U.S.EPA, 2005). IARC considers the chlorophenoxyacetic acids group of chemicals as possibly carcinogenic to humans. Additional information is available from U.S.EPA at: https://www.epa.gov/pesticides/.

Biomonitoring Information

Urinary levels of 2,4-D reflect recent exposure. The 95th percentiles of the NHANES 1999-2000 and 2001-2002 subsamples were roughly similar to the 95th percentile values reported in a nonrandom subsample from NHANES III (1988-1994) (CDC, 2009; Hill et al., 1995). In previous samples of the U.S. population (Hill et al., 1995; Kutz et al., 1992) and in a small sample of children (Hill et al., 1989) and of adults and children (Baker et al., 2000), urinary 2,4-D levels were detectable in less than a quarter of the individuals studied.

2,4-D production plant workers and a few forestry workers spraying 2,4-D had urinary levels several hundred to several thousand times higher than the 95th percentiles of the NHANES subsamples (CDC, 2009; Frank et al., 1985; Kolmodin-Hedman and Erne, 1980; Knopp et al., 1994). Average post-application urinary levels of 2,4-D in farmers were more than 25-fold higher than the 95th percentiles in the NHANES 1999-2000 and 2001-2002 subsamples (Arbuckle et al., 2005; CDC, 2009). Post-application levels in farmers and home gardeners were observed to be dependent on the time since application, amount of pesticide applied, the number of acres to which it was applied (Curwin et al., 2005), and the use protective clothing or equipment (Arbuckle et al., 2005; Harris et al., 1992). In farm families, geometric mean urinary levels of 2,4-D were highest in the farmers who applied the 2,4-D; other family members had levels ranging only slightly higher than the 95th percentile levels in NHANES 1999-2000 and 2001-2002 subsamples (CDC, 2009; Mandel et al., 2005).

Finding a measurable amount of 2,4-D in urine does not imply that the level of the 2,4-D will result in an adverse health effect. Biomonitoring studies of 2,4-D in urine provide physicians and public health officials with reference values so that they can determine whether other people have been exposed to higher levels of 2,4-D than levels found in the general population. Biomonitoring data can also help scientists plan and conduct research on exposure and health effects.

References

Arbuckle TE, Cole DC, Ritter L, Ripley BD. Biomonitoring of herbicides in Ontario farm applicators. Scand J Work Environ Health 2005;31 Suppl 1:90-7.

Arnold EK, Beasley VR. The pharmacokinetics of chlorinated phenoxy acid herbicides: a literature. Vet Hum Toxicol 1989;31(2):121-5.

Baker SE, Barr DB, Driskell WJ, Beeson MD, Needham LL. Quantification of selected pesticide metabolites in human urine using isotope dilution high-performance liquid chromatography/tandem mass spectrometry. J Expo Anal Environ Epidemiol 2000;10(6 Pt 2):789-98.

Centers for Disease Control and Prevention (CDC). Fourth National Report on Human Exposure to Environmental Chemicals, 2009. [online] Available at URL: https://www.cdc.gov/exposurereport/. 10/15/12

Charles JM, Hanley TR Jr, Wilson RD, van Ravenzwaay B, Bus JS. Developmental toxicity studies in rats and rabbits on 2,4-dichlorophenoxyacetic acid and its forms. Toxicol Sci 2001;60(1):121-31.

Curwin BD, Hein MJ, Sanderson WT, Barr DB, Heederik D, Reynolds SJ, et al. Urinary and hand wipe pesticide levels among farmers and nonfarmers in Iowa. J Expo Anal Environ Epidemiol 2005 Nov;15(6):500-8.

Frank R, Campbell RA, Sirons G J. Forestry workers involved in aerial application of 2,4-dichlorophenoxyacetic acid (2,4-D): exposure and urinary excretion. Arch Environ Contam Toxicol 1985;4:427-35.

Garabrant DH, Philbert MA. Review of 2,4-dichlorophenoxyacetic acid (2,4-D) epidemiology and toxicology. Crit Rev Toxicol 2002;32(4):233-57.

Harris SA, Solomon KR, Stephenson GR. Exposure of homeowners and bystanders to 2,4 dichlorophenoxyacetic acid (2,4-D). J Environ Sci Health B 1992;27(1):23-38.

Hazardous Substances Database (HSDB). 2,4 dichlorophenol. Environmental fate/exposure summary. Last revised 08/20/2009. Available online at: https://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB. 1/24/2013

Hill RH Jr, To T, Holler JS, Fast DM, Smith SJ, Needham LL, et al. Residues of chlorinated phenols and phenoxy acid herbicides in the urine of Arkansas children. Arch Environ Contam Toxicol 1989;18(4):469-74.

Hill RH Jr, Head SL, Baker S, Gregg M, Shealy DB, Bailey SL, et al. Pesticide residues in urine of adults living in the United States: reference range concentrations. Environ Res 1995;71(2):99-108.

International Programme on Chemical Safety-INCHEM (IPCS). Pesticides residues in food: 1996 evaluations Part II Toxicology. 914. Dichlorophenoxyacetic acid, 2,4-. Available at URL: http://www.inchem.org/documents/jmpr/jmpmono/v96pr04.htm. 1/24/13

Institute of Medicine (IOM). Board on Health Promotion and Disease Prevention. Committee to Review the Health Effects in Vietnam Veterans of Exposure to Herbicides (Fourth Biennial Update. Veterans and Agent Orange: update 2002. Washington (DC): National Academies Press. 2003. Available at URL: http://www.nap.edu/catalog.php?record_id=10603. 10/15/12

Knopp D. Assessment of exposure to 2,4-dichlorophenoxyacetic acid in the chemical industry: results of a five year biological monitoring study. Occup Environ Med 1994;51(3):152-9.

Kohli JD, Khanna RN, Gupta BN, Dhar MM, Tandon JS, Sircar KP. Absorption and excretion of 2,4-dichlorophenoxyacetic acid in man. Xenobiotica 1974;4:97-100.

Kolmodin-Hedman B, Erne K. Estimation of occupational exposure to phenoxy acids (2,4-D and 2,4,5-T). Arch Toxicol Suppl 1980;4:318-21.

Kutz FW, Cook BT, Carter-Pokras OD, Brody D, Murphy RS. Selected pesticide residues and metabolites in urine from a survey of the U.S. general population. J Toxicol Environ Health 1992;37(2):277-91.

Mandel JS, Alexander BH, Baker BA, Acquavella JF, Chapman P, Honeycutt R. Biomonitoring for farm families in the farm family exposure study. Scand J Work Environ Health. 2005;31 Suppl 1:98-104.

National Toxicology Program (NTP). TOX-63: TOXICITY REPORT CURVES. Tables, Survival and Growth Curves from NTP Toxicity Studies. TOX-63 Peroxisone Project (2,4-Dichlorophenoxyacetic Acid). Updated March 7, 2006. Available at URL: https://ntp.niehs.nih.gov/index.cfm?objectid=06FF8DA6-E5A1-90CD-3F26562CEC5CDDE5. 10/15/12

Sauerhoff MW, Braun WH, Blau GE, Gehring PJ. The fate of 2,4-dichlorophenoxyacetic acid (2,4-D) following oral administration to man. Toxicology 1977;8:3-11.

U.S. Environmental Protection Agency (U.S.EPA). 2,4-D RED Facts. June 2005. EPA 738 F-05-002. Available at URL: https://www.epa.gov/oppsrrd1/REDs/factsheets/24d_fs.htm. 10/15/12

U. S. Environmental Protection Agency (U.S.EPA). Office of Prevention Pesticides and Toxic Substances. Pesticide industry sales and usage - 2000 and 2001 market estimates. Washington (DC): U.S.EPA. May, 2004. Available at URL: https://www.epa.gov/pesticides/pestsales/01pestsales/market_estimates2001.pdf . 10/15/12

U.S. Geological Survey (USGS). ). The Quality of Our Nation's Waters Pesticides in the Nation's Streams and Ground Water, 1992-2001. Circular 1291. Supplemental Technical Information (available on-line only). March 2006, revised February 15, 2007. Available at URL: https://water.usgs.gov/nawqa/pnsp/pubs/circ1291/supporting_info.php. 10/15/12