2,4-Dichlorophenoxyacetic acid (2,4-D)

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Studies and Reports

  • Alexander B et al., Biomonitoring data for 2,4-dichlorophenoxyacetic acid in the United States and Canada: interpretation in a public health risk assessment context using Biomonitoring Equivalents, Environ Health Perspect. 2010 Feb;118(2):177-81.
    • Conclusions. "Biomonitoring data from these studies indicate that current exposures to 2,4-D are below applicable exposure guidance values. This review demonstrates the value of biomonitoring data in assessing population exposures in the context of existing risk assessments using the BE approach. Risk managers can use this approach to integrate the available biomonitoring data into an overall assessment of current risk management practices for 2,4-D."
  • Hartge P et al., Residential herbicide use and risk of non-Hodgkin lymphoma, Cancer Epidemiol Biomarkers Prev. 2005 Apr;14(4):934-7.
    • Conclusion. "We found no detectable excess associated with residential exposures. Residential herbicide exposures are unlikely to explain the long-term increase in NHL."
  • Solomon K et al., Nonagricultural and residential exposures to pesticides, Scand J Work Environ Health. 2005;31 Suppl 1:74-81; discussion 63-5.
    • Abstract. "Epidemiologic studies and risk assessments conducted to assess the chronic effects of pesticides are limited by inadequate measurements of pesticide exposures, and surrogates for these data are frequently used. In this paper, pesticide use and absorbed dose previously measured in residential and occupational settings are used to evaluate the hypothesis that there is a relationship between pesticide use and exposure. For homeowner applicators of 2,4-dichlorophenoxyacetic acid (2,4-D) and chlorpyrifos, exposures were poorly correlated with the amount of herbicide used (r2 = 0.01 to 0.40); however, exposures from a granular product were consistently less than those with liquid formulation. For professional landscape applicators, exposure over 14 days and 7 days of use was poorly correlated with the amount of 2,4-D sprayed (r2 = 0.17 and 0.21, respectively). However, inclusion of the type of spray nozzle used and the use of gloves while spraying in the model explained increased predictability and explained 68% of the variation."
  • Garabrant D, Review of 2,4-dichlorophenoxyacetic acid (2,4-D) epidemiology and toxicology, Crit Rev Toxicol. 2002 Jul;32(4):233-57.
    • Abstract. "The scientific evidence in humans and animals relevant to cancer risks, neurologic disease, reproductive risks, and immunotoxicity of 2,4-D was reviewed. Despite several thorough in vitro and in vivo animal studies, no experimental evidence exists supporting the theory that 2,4-D or any of its salts and esters damages DNA under physiologic conditions. Studies in rodents demonstrate a lack of oncogenic or carcinogenic effects following a lifetime dietary administration of 2,4-D. Epidemiologic studies provide scant evidence that exposure to 2,4-D is associated with soft tissue sarcoma, non-Hodgkin's lymphoma, Hodgkin's disease, or any other cancer. Overall, the available evidence from epidemiologic studies is not adequate to conclude that any form of cancer is causally associated with 2,4-D exposure. There is no human evidence of adverse reproductive outcomes related to 2,4-D. The available data from animal studies of acute, subchronic, and chronic exposure to 2,4-D, its salts, and esters show an unequivocal lack of systemic toxicity at doses that do not exceed renal clearance mechanisms. There is no evidence that 2,4-D in any of its forms activates or transforms the immune system in animals at any dose. At high doses, 2,4-D damages the liver and kidney and irritates mucous membranes. Although myotonia and alterations in gait and behavioral indices are observed after overwhelming doses of 2,4-D, alterations in the neurologic system of experimental animals are not observed with the administration of doses in the microgram/kg/day range. It is unlikely that 2,4-D has any neurotoxic potential at doses below those required to induce systemic toxicity."
  • Burns C et al., Mortality in chemical workers potentially exposed to 2,4-dichlorophenoxyacetic acid (2,4-D) 1945-94: an update, Occup Environ Med. 2001 Jan;58(1):24-30.
    • Conclusion. "There was no evidence of a causal association between exposure to 2,4-D and mortality due to all causes and total malignant neoplasms. No significant risk due to NHL was found. Although not an initial hypothesis, an increased relative risk of ALS was noted. This finding is unsupported by other animal and human studies."
  • Fleming L et al., Mortality in a cohort of licensed pesticide applicators in Florida, Occup Environ Med. 1999 Jan;56(1):14-21.
    • Results and Conclusions. RESULTS: The pesticide applicators were consistently and significantly healthier than the general population of Florida. As with many occupational cohorts, the risks of cardiovascular disease and of diseases associated with alcohol and tobacco use were significantly lower, even in the subpopulations--for example, men, women, and licence subcategories. Among male applicators, prostate cancer mortality (SMR 2.38 (95% confidence interval (95% CI) 1.83 to 3.04) was significantly increased. No cases of soft tissue sarcoma were confirmed in this cohort, and non-Hodgkin's lymphoma was not increased. The number of female applicators was small, as were the numbers of deaths. Mortality from cervical cancer and breast cancer was not increased. Additional subcohort and exposure analyses were performed. CONCLUSIONS: Consistent with previous publications on farmers but at odds with current theories about the protective effects of vitamin D, prostate cancer was increased in these pesticide applicators. Female breast cancer was not increased despite theories linking risk of breast cancer with exposure to oestrogen disruptors--such as the organochlorines. The lack of cases of soft tissue sarcoma is at odds with previous publications associating the use of the phenoxy herbicides with an increased risk of these cancers."
  • Asp S et al., Mortality and cancer morbidity of Finnish chlorophenoxy herbicide applicators: an 18-year prospective follow-up, Am J Ind Med. 1994 Aug;26(2):243-53.
    • Abstract. "An 18-year follow-up for mortality and cancer morbidity was conducted in a cohort of 1,909 men who had started spraying chlorophenoxy herbicides (mixture of 2,4-dichlorophenoxyacetic acid [2,4-D] and 2,4,5-trichlorophenoxyacetic acid [2,4,5-T]) in 1955 through 1971. In all, 384 persons had died during the follow-up, and there was a slight deficit in natural deaths (standardized mortality ratio [SMR] 0.84; 95% confidence interval [CI] 0.75-0.94). By contrast, there was a small, nonsignificant increase in accidental and violent deaths. The overall cancer mortality was slightly less than in the general population (SMR 0.83; 95% CI 0.65-1.02), and not a single case of death of non-Hodgkin's lymphomas (NHL) or soft tissue sarcomas (STS) was detected. With regard to cancer morbidity, the incident cases showed a slight deficit compared to the population figure (standardized incidence ratio [SIR] 0.81; 95% CI 0.67-0.97). One case of NHL was found (2.4 expected with 10 years of latency), but not a single case of STS (0.8 expected with 10 years of latency). While our study does not support the contention that spraying of 2,4-D and 2,4,5-T containing herbicides carries any significant risk of cancer, the medium to low statistical power of the study does not allow any far reaching negative conclusions regarding the carcinogenicity of the agents."
  • Kogevinas M et al., Cancer incidence and mortality in women occupationally exposed to chlorophenoxy herbicides, chlorophenols, and dioxins, Cancer Causes Control. 1993 Nov;4(6):547-53.
    • Abstract. "The association between exposure to chlorophenoxy herbicides contaminated with dioxins and occurrence of cancer has been studied mainly in male populations. In animal experiments, gender differences have been recorded in the cancer response to administered 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Mortality and cancer incidence in an international cohort of 701 women from an International Register of Workers occupationally exposed to chlorophenoxy herbicides, chlorophenols, and dioxins is examined. Cause-specific, national death rates and cancer incidence rates were used as referents. Cancer risk was not increased overall, with a standardized incidence ratio (SIR) of 96 and 95 percent confidence interval (CI) of 64-137, based on 29 cases. Among workers exposed to those chlorophenoxy herbicides contaminated with TCDD, excess cancer incidence (for all sites) was observed (SIR = 222, CI = 102-422, 9 cases); this was highest in the first 10 years after exposure. No excess was observed for breast cancer, the most common cancer in this cohort. Results on cancer mortality were consistent with those on incidence."
  • Bueno de Mesquita H et al., Occupational exposure to phenoxy herbicides and chlorophenols and cancer mortality in The Netherlands, Am J Ind Med. 1993 Feb;23(2):289-300.
    • Abstract. "As part of the "IARC International Register of Persons Exposed to Phenoxy Herbicides and Contaminants," a cohort of workers who manufacture and prepare chlorophenoxy herbicides was recruited in The Netherlands. The cohort comprised 2,310 workers from two plants, operated by different companies, who were followed during the periods 1955-1985 and 1965-1986, respectively. In 1963, there had been an industrial accident in one factory with concomitant release of dioxin into the environment. Loss to follow-up was 3%. Mortality data on 963 exposed and 1,111 nonexposed men were evaluated by external and internal comparison. Compared with national rates, total mortality (94 deaths, standardized mortality ratio [SMR] = 101; 95% confidence interval [CI], 82-124) and cancer mortality (31 deaths, SMR = 107; 95% CI, 73-152) for exposed workers were not significantly increased. A statistically insignificant increase was observed for non-Hodgkin's lymphoma (2 deaths, SMR = 299; 95% CI, 36-1,078). No cases of soft-tissue sarcoma were encountered. There was no increase in either total mortality (25 deaths, SMR = 111; 95% CI, 72-163) or cancer mortality (10 deaths, SMR = 137; 95% CI, 66-252) among the 139 workers probably exposed to dioxins during the 2,4,5-trichlorophenol production accident or the subsequent clean-up operations. Compared with nonexposed workers, exposed workers did not exhibit a higher total mortality (rate ratio [RR] = 1.28; 95% CI, 0.89-1.82). Mortality due to all cancers (RR = 1.7; 95% CI, 0.9-3.4) and respiratory cancer (RR = 1.7; 95% CI, 0.5-6.3) was insignificantly elevated. These findings suggest that the increases in cancer mortality among workers exposed to phenoxy herbicides and chlorophenols may be attributable to chance. Lack of power prevented evaluation with respect to specific cancers."
  • Harris S et al., Exposure of homeowners and bystanders to 2,4-dichlorophenoxyacetic acid (2,4-D), J Environ Sci Health B. 1992 Feb;27(1):23-38.
    • Abstract. "Total body dose received in home gardeners applying 2,4-D and bystanders living within the household, but not applying the pesticide was measured. Levels of 2,4-D were monitored in air samples both inside the home and downwind of the application site. Homeowners were divided into protective and non-protective apparel groups and applied both a granular and liquid formulation of 2,4-D on two separate dates. Analyses of urine collected from homeowners for 96 hours following applications found total body doses ranging from non-detectable to 0.0071 mg/kg of body weight. The highest exposures occurred in the non-protected group and were consistently associated with spills of the liquid concentrate or excessive contact with the dilute mixture on the hands or forearms. Residues of 2,4-D were not detected in urine samples supplied by bystanders to home applicators. Residues of 2,4-D were detected in five of the 76 air samples taken during the home applications. Two of these air samples coincided with measurable applicator exposure but it is unlikely that this was a major route of exposure."
  • Harris S et al., Human exposure to 2,4-D following controlled activities on recently sprayed turf., J Environ Sci Health B. 1992 Feb;27(1):9-22.
    • Abstract. "Total body dose of 2,4-D was determined in 10 volunteers following exposure to sprayed turf 1 hour following application and in 10 volunteers exposed 24 hours following application. Each group of 10 volunteers was divided in half and five wore long pants, a short-sleeved shirt, socks and closed footwear. The other five wore shorts and a short-sleeved shirt and were barefoot. All volunteers were exposed to a 2 by 15 m area of turf for 1 hour during which they alternated between walking and sitting or lying on the turf surface for intervals of 5 minutes. Dislodgeable residues of 2,4-D taken during the exposure sessions showed a rapid decline from 1 hour following application (8%) to 24 hours following application (1%). No detectable residues were found in 4-day urine samples supplied by volunteers except for 3 people who were barefoot and wearing shorts and contacted the turf 1 hour following 2,4-D application. The highest dose was measured in a volunteer who removed his shirt for 30 minutes of the exposure session (426 micrograms). Exposure levels of the other two volunteers who wore the prescribed clothing were lower (153 and 103 micrograms). No detectable residues were found in urine samples supplied by volunteers exposed to sprayed turf 24 hours following application. These results indicate that at the doses measured, exposure to sprayed turf should present little risk in humans. However, people can reduce exposure to non-detectable levels by remaining off treated turf for a period of 24 hours or until after rainfall or irrigation so that dislodgeable residues and therefore potential exposure are essentially zero."
  • Ibrahim M et al., Weight of the evidence on the human carcinogenicity of 2,4-D, Environ Health Perspect. 1991 Dec;96:213-22.
    • Abstract. "The phenoxy herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) is widely used to control the growth of weeds and broadleaf plants. We convened a panel of 13 scientists to weigh the evidence on the human carcinogenicity of 2,4-D. The panel based its findings on a review of the toxicological and epidemiological literature on 2,4-D and related phenoxy herbicides. The toxicological data do not provide a strong basis for predicting that 2,4-D is a human carcinogen. Although a cause-effect relationship is far from being established, the epidemiological evidence for an association between exposure to 2,4-D and non-Hodgkin's lymphoma is suggestive and requires further investigation. There is little evidence of an association between use of 2,4-D and soft-tissue sarcoma or Hodgkin's disease, and no evidence of an association between 2,4-D use and any other form of cancer. Scientists on the panel were asked to categorize 2,4-D as a "known," "probable," "possible," or "unlikely" carcinogen or as a noncarcinogen in humans. The predominant opinion among the panel members was that the weight of the evidence indicates that it is possible that exposure to 2,4-D can cause cancer in humans, although not all of the panelists believed the possibility was equally likely: one thought the possibility was strong, leaning toward probable, and five thought the possibility was remote, leaning toward unlikely. Two panelists believed it unlikely that 2,4-D can cause cancer in humans."
  • Saracci R et al., Cancer mortality in workers exposed to chlorophenoxy herbicides and chlorophenols, Lancet. 1991 Oct 26;338(8774):1027-32.
    • Abstract. "Epidemiological studies have revealed an increased risk of cancer, notably soft-tissue sarcomas and non-Hodgkin's lymphomas, in people occupationally exposed to chlorophenoxy herbicides, including those contaminated by 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD). We report here a historical cohort study of mortality in an international register of 18,910 production workers or sprayers from ten countries. Exposure was reconstructed through questionnaires, factory or spraying records, and job histories. Cause-specific national death rates were used as reference. No excess was observed in all-cause mortality, for all neoplasms, for the most common epithelial cancers, or for lymphomas. A statistically non-significant two-fold excess risk, based on 4 observed deaths, was noted for soft-tissue sarcoma with a standardised mortality ratio (SMR) of 196 and 95% confidence interval (Cl) 53-502; this was concentrated as a six-fold statistically significant excess, occurring 10-19 years from first exposure in the cohort as a whole (SMR = 606 [165-1552]) and, for the same time period, as a nine-fold excess among sprayers (SMR = 882 [182-2579]). Risks appeared to be increased for cancers of the testicle, thyroid, other endocrine glands, and nose and nasal cavity, based on small numbers of deaths. The excess of soft-tissue sarcomas among sprayers is compatible with a causal role of chlorophenoxy herbicides but the excess does not seem to be specifically associated with those herbicides probably contaminated by TCDD."
  • Bond G et al., Phenoxy herbicides and cancer: insufficient epidemiologic evidence for a causal relationship, Fundam Appl Toxicol. 1989 Jan;12(1):172-88.
    • Abstract. "The question as to whether or not any or all of the phenoxy herbicides are carcinogenic to humans continues to be evaluated. We review the evidence available from the retrospective cohort and case-control epidemiology studies. Graphs of the individual probability densities for the odds ratios from the eight case-control studies of soft-tissue sarcoma, Hodgkin's disease, or non-Hodgkin's lymphoma demonstrate gross inconsistencies which are not likely to be attributable to chance. Early studies, conducted in Sweden, had indicated strong associations, but subsequent work from New Zealand and the United States has failed to substantiate those findings. The reasons for the discordant results may relate more to methodologic problems in the earlier studies than to qualitative or quantitative differences in the exposures of the underlying populations. The retrospective cohort studies offer the advantage of having focused on occupational groups believed to have had the highest exposures, although they have been criticized as being individually too small to assess the risks of the rarer forms of cancer. Consideration of the combined cohort studies of workers exposed to the phenoxy herbicides per se provides little or no evidence of carcinogenicity. Thus, the total weight of evidence currently available does not support a conclusion that the phenoxy herbicides present a carcinogenic hazard to humans."
  • Vineis P et al., Phenoxy herbicides and soft-tissue sarcomas in female rice weeders. A population-based case-referent study, Scand J Work Environ Health. 1987 Feb;13(1):9-17.
    • Abstract. "A population-based case-referent study was conducted in an area of northern Italy where rice growing is the predominant agricultural activity and phenoxy herbicides have been used since 1950. Manual rice weeding was formerly performed by a seasonal female working population; in the early 1950s these women were concurrently exposed to chemical herbicides. Sixty-eight persons representing incident and histologically revised cases (31 women) and 158 population referents (73 women) were interviewed. The cases were histologically confirmed independently by two blinded pathologists, and exposure to phenoxy herbicides was assessed by two blinded pesticide researchers. An age-adjusted odds ratio of 0.91 was found for the living men (with suspect exposures; no man diagnosed as a case had been exposed with certainty to phenoxy herbicides). Among the living women the relative risk was 2.7 (90% confidence interval 0.59-12.37), and it further increased when attention was restricted to women exposed in the whole 1950-1955 period and to younger age groups.
  • Pearn J, Herbicides and congenital malformations: a review for the paediatrician, Aust Paediatr J. 1985 Nov;21(4):237-42.
    • Abstract. "The herbicides 2, 4, 5-T and 2, 4-D are relatively non-toxic to primates, in acute exposure. Dioxins, which have occurred as impurities in these two herbicides, manifest universal biological toxicity. The best understood dioxin TCDD, has, in susceptible strains of mice, a very low teratogenic minimal effective dose of 1-10 micrograms/kg. This fact has engendered an era of uncertainty about the potential teratogenic effects of herbicides, in the context of potential human exposure. This paper reviews current knowledge concerning herbicide teratogenesis following maternal exposure. Because of species specificity of teratogenic agents, it is not possible to extrapolate from effects in lower animals to potential effects in humans. It remains a fact however that all proven human teratogens have parallel animal models. Following maternal exposure to herbicides and to dioxins, it has not been possible to produce teratogenic effects in primates, although fertility may be affected. Epidemiological reports from Hungary, Italy (the ICMESA accident), New Zealand, the United States, Europe and Australia have not revealed any positive evidence to indicate that a human herbicide teratogenic syndrome exists."
  • Riihimaki V et al., Mortality of 2,4-dichlorophenoxyacetic acid and 2,4,5-trichlorophenoxyacetic acid herbicide applicators in Finland: first report of an ongoing prospective cohort study, Scand J Work Environ Health. 1982 Mar;8(1):37-42.
    • Abstract. "Some recent epidemiologic studies have suggested that chlorinated phenoxy acid herbicides are human carcinogens. The mortality experience in a cohort of 1,926 men who had sprayed 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) during 1955-1971 has been followed prospectively from 1972 to 1980. The total phenoxy acid exposure was generally rather low because the duration of work had mostly been less than two months. In 1972-1976 mortality from all natural causes in the cohort was only 54% of the expected value (based on age-specific rates for the general population), and in the succeeding 4-a period 81% of the expected value. In the assessment of cancer, mortality allowance was made for 10- and 15-a periods of latency between the first exposure and the start of the recording of vital status during the follow-up. No increase in cancer mortality was detected, and the distribution of cancer types was unremarkable. No cases of death from lymphomas or soft tissue sarcomas were found. The study results must, however, be viewed with great caution owing to the small size of the cohort, the low past exposure, and the brief follow-up period."

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