COOPERATIVE EXTENSION UNIVERSITY OF CALIFORNIA ENVIRONMENTAL TOXICOLOGY NEWSLETTER

COOPERATIVE EXTENSION UNIVERSITY OF CALIFORNIA
ENVIRONMENTAL TOXICOLOGY NEWSLETTER

Vol. 1 No. 1 November 14, 1980

This newsletter is the first of what I hope will be a long, fruitful, series dealing with current problems in Environmental Toxicology. Environmental Toxicology deals with natural and synthetic poisons and their occurrence, distribution, fate in, and effects on the environment. This idea is expressed well in our logo which was created by Harry Troughton of Visual Media, Davis campus. Land, air, water, plants, wildlife, domestic animals and human beings are all included. Since this doesn't leave much out, I can include practically anything. I would appreciate your feedback on the content of these newsletters so that I can provide you with the information you need. In order to get off to a good start, the topic of this first newsletter is 2,4-D.

2,4-D

In April of this year, the EPA published a Fact Sheet on 2,4-D. In June, the Hazard Alert System (HALTS), Epidemiological Studies Laboratory, for the State of California Department of Health Services published a report entitled, "2,4-Dichlorophenoxyacetic acid (2,4-D): Evaluation of the Human Health Hazards". If you are interested in getting your own copy, it can be obtained from the Epidemiological Studies Laboratory, State of California, Department of Health Services, 2151 Berkeley Way, Berkeley, CA 94707. As stated in the introduction of this report, it was prepared "to provide interested individuals and agencies with complete and up-to-date information on the known and projected human health hazards of 2,4-D." My personal evaluation of this document is that it falls short of accomplishing those goals. My evaluation is based on a comparison of the report with primary source materials obtained from the Environmental Toxicology Department Library files on 2,4-D, and the University of California, Davis, Health Sciences Library.

Because the HALTS Report has received considerable publicity recently, I think it is of particular interest to compare the HALTS Conclusions and Recommendations to the Summary of Toxicology Review published in the EPA Fact Sheet of April, 1980. The Summary of Toxicology Review from the EPA Fact Sheet and the HALTS Conclusions and Recommendations are printed below for your information.

SUMMARY OF TOXICOLOGY REVIEW (EPA)

Most of the data in EPA files on the potential health effects of 2,4-D are centered on the acid form, even though there are many derivatives, such as salts and esters. This is because the many forms of 2,4-D metabolize to the acid form in the environment and in the body. The discussion of animal data below, therefore, concerns the acid form of 2,4-D unless otherwise noted.

1. Acute toxicity. Low to moderate. The potential for immediate poisonings from contact with the chemical is unlikely.
2. Neurotoxicity. There is little definitive information on the possible neurological effects of 2,4-D. In several reported cases of impaired nerve function, it was not known if the individuals were peculiarly sensitive to that type of effect or were exposed to other toxic materials.
3. Reproductive effects (effects on the unborn). Tests have been conducted on rats, mice and hamsters to evaluate the possible reproductive effects of 2,4-D. In almost all tests, no observable effect level has been established. 2,4-D causes some of the less serious fetotoxic effects, such as edema (swelling of tissues) at the lower dose levels tested, and causes life-threatening birth defects (skeletal malformations) and cleft palates only at the very high levels tested. Based on the no observable effect levels in the animal studies, EPA estimates that the level of exposure in a "worst case" situation (eg. a person standing directly under a spray plane) would be 500 to 1000 times less than the dose level that might cause an effect.
Much of the data available to judge these effects was generated by old study protocols, has deficiencies in the test methods, and needs clarification by further study. EPA also reviewed summaries of tests conducted in the Soviet Union which state that some derivatives of 2,4-D produced adverse effects on unborn animal fetuses at much lower levels than indicated by the data in EPA's files. These summaries could not be used in the Agency's review because the identity of the test materials, and its impurities, was unclear, and because there were no numerical data to back up the summary conclusions. In some cases tests need to be done on specific derivatives of 2,4-D.
4. Oncogenicity (potential for causing tumors). Several rodent studies have been conducted to date. The tests were conducted a decade ago and are considered to be inadequate and inconclusive by today's scientific standards. New studies on rodents are needed.
5. Mutagenicity (inheritable effects). The vast majority of the mutagenicity studies conducted on 2,4-D are negative. However, there are three positive studies. Taken as a group, the results of the studies can be described as inconsistent and inconclusive. New series of tests being conducted by the Department of Health, Education, and Welfare will be reviewed byEPA when they are completed.
6. Epidemiology. No epidemiological studies of human health effects from 2,4-D exposure have been completed. However, EPA is currently investigating reports about alleged adverse effects from potential chemical exposure in several parts of the country. EPA will be looking at the results of those studies and will decide in the near future about additional field work.

(From the EPA 2,4-D Fact Sheet of April, 1980.)

The HALTS Conclusions and Recommendations are printed below for comparison.

CONCLUSIONS AND RECOMMENDATIONS (HALTS)

Exposure to 2,4-D has caused peripheral neuropathy. Additional cases of peripheral neuropathy may not have been correctly diagnosed. Animal studies suggest a potential risk of cancer and a possible low-level hazard of birth defects in humans. Though the degree of risk to humans following exposure to 2,4-D cannot now be estimated, the following recommendations are made as minimal precautions to protect the public health.

1. Current work practices are inadequate to protect against potential neurotoxicity. They should be reviewed and corrected.
2. The scientific data are sufficiently suggestive of a carcinogenic effect, and demonstrate a weak teratogenic effect, that 2,4-D use should be restricted to areas in which human exposure can be kept to the minimum. Contamination of open water must be monitored and prevented. Broadcast methods of application that could directly expose the general population should be strongly discouraged. Greater consideration must be given to alternative methods for removing unwanted plants.
3. Products containing 2,4-D should be labeled to warn users of the herbicide's potential for causing neurotoxicity and how to protect against it. Present labels are inadequate. Educational information should be provided for anyone who works with the substance.
4. Home gardeners using products containing 2,4-D should exercise care to avoid skin exposure to themselves or others.
5. Adequate tests in rodents should be conducted following National Cancer Institute protocol to determine the carcinogenicity of 2,4-D. Studies should also be conducted to measure the 2,4-D excretion in urine and peripheral nerve function in exposed workers.

[From "2,4-Diphenoxacetic Acid (2,4-D): Evaluation of the Human Health Hazards, by the Hazard Alert System, June 16, 1980.]

Let us begin our comparison of the two reports with the points upon which they agree. Both agree that 2,4-D is of low acute toxicity. Both agree that 2,4-D is a weak teratogen and that very high dose levels are needed to demonstrate teratogenic effects in experimental animals. The two reports also agree that further testing should be done to evaluate the carcinogenicity of 2,4-D in rodents. Todays criteria for carcinogenicity testing were not fulfilled by the past tests, thus the results are inconclusive. Although not included in what is reprinted here, both reports also agree that the synthesis of 2,4-D is different from the synthesis of 2,4,5-T and that 2,4-D does not contain the isomer of TCDD (a highly toxic dioxin contaminant) that is found in 2,4,5-T.

There is very recent evidence that 2,4-D may contain a dioxin contaminant that is different from that found in 2,4,5-T. Preliminary studies in Canada showed that the dioxin isomer present in 2,4-D was much less toxic than the isomer of dioxin found in 2,4,5-T. The final results and conclusions are not yet in. (I will include updates on 2,4-D in subsequent newsletters.)

The reports differ with respect to their evaluations of neurotoxicity and carcinogenicity data. EPA states "There is little definitive information on the possible neurological effects of 2,4-D." HALTS states "It's (neurotoxicity) occurrence should be regarded as a distinct possibility following even minimal exposure to the skin or following oral ingestion." I have read the literature of the seven reported 2,4-D neurotoxicity cases. In my evaluation one case does not correspond at all with the other six with respect to onset, symptoms, progression of illness and recovery. The other six are very similar and involved dermal exposure to 2,4-D without washing it off. The symptoms of neurotoxicity were paresthesias (tingling sensations, numbness, shooting pains) like those that occur when your foot "falls asleep" or you bump your "funny bone." These symptoms progressed in some cases to severe weakness and temporary paralysis. Recovery was slow and not always complete.

Based on my evaluation of the case reports, I have to agree with EPA for the most part. I think the six cases might have been idiosyncratic (very unusual) or hypersensitive toxic responses to excessive 2,4-D exposure. Exposure to other chemicals was not ascertained and remains a distinct possibility. All of these cases, with the exception of the HALTS case, were reported 15 or more years ago. The incidence of this type of occurrence is most likely very low if only 6 cases have been documented in over 35 years of 2,4-D use. HALTS suggests that the incidence may be much higher. Mild symptoms of neuropathy might go unreported particularly if they did not cause loss of function but the severe types of symptoms reported (shooting pains, paralysis) are not the types of symptoms that people would ignore, particularly if the symptoms persist.

HALTS recommends that 2,4-D excretion and peripheral nerve function tests be conducted in exposed workers. Excretion tests in workers have been carried out in Sweden, and were used to correlate exposure to 2,4-D with urinary excretion of 2,4-D. I think that properly performed peripheral nerve function tests of workers exposed to 2,4-D would provide some interesting information. I do not think such studies are urgently needed, but I would like to see them done in association with exposure and urinary excretion studies. Such a study would minimize factors which confound retrospective epidemiological studies. Retrospective epidemiological studies can only associate 2,4-D exposure with neuropathy, and not prove a cause-effect relationship.

I would like to point out one last area from the HALTS report that you might hear about. It has to do with the inclusion of and reference to data on 2,4-D carcinogenicity testing by Reuber (1979). All of Reuber's results included in the HALTS report are from a personal communication. A personal communication can be a letter, a note or a phone call. What is important is that a personal communication has not undergone the type of peer review that published reports are subjected to, and thus to me its inclusion, and the emphasis placed upon it in the HALTS report is misleading. The tables of data from Reuber published in Appendix of the HALTS report are meaningless without a proper presentation and evaluation of Reuber's methodology. The EPA calls the carcinogenicity data "inconclusive", HALTS calls it "suggestive". I have to agree with the EPA's choice of words in this case.

If the use of 2,4-D in your county is a controversial topic you may hear about the HALTS Report. I hope this general information will be of use to you in answering questions about it. Some of the issues addressed in this letter are the ones I feel may be most misrepresented. Please contact me if you have any specific questions concerning the information provided, or if there is anything I can do to help clear up misunderstandings arising from it or any other source.

Arthur L. Craigmill, Ph.D
Extension Toxicologist
Environmental Toxicology and Veterinary Extension
University of California
Davis, CA 95616