Benomyl

This fact sheet summaries the important health and environment effects of the fungicide benomyl. It came to the public's attention in the early 1990s because the exposure of pregnant women to benomyl was linked with subsequent eye defects in the foetus.

What is benomyl
Benomyl was first reported as a fungicide in 1968 and introduced onto the UK market in 1971 by the US company Du Pont(1). It is a systemic benzimidazole fungicide that is selectively toxic to micro-organisms and to invertebrates, especially earthworms(2).
    Benomyl and its main metabolite carbendazim bind to microtubules (an essential structure of all cells) and therefore interfere with cell functions such as cell division and intracellular transportation. The selective toxicity of benomyl as a fungicide is possibly due to its heightened effect on fungal rather than mammalian microtubules(3).

Uses and usage
Benomyl is used as a pre-harvest systemic fungicide, and as a post-harvest dip or dust. It combats a wide range of fungal diseases of arable and vegetable crops, apples, soft fruit, nuts, ornamentals, mushrooms, lettuce, tomatoes and turf. It is also available widely for amenity and amateur garden use(4). Benomyl's principal trade name is Benlate.
    The basic manufacturer is Du Pont Agricultural Products, based in Wilmington, Delaware. Global figures of benomyl usage are not widely available. In Britain benomyl was applied to 22,157 ha of top fruit crops (1992)(5); 2,957 ha of bulb and flower crops (1994)(6); 1,359 ha of outdoor vegetable crops (1995)(7) and 1,033 ha of hardy nursery stock (1993)(8).

Acute toxicity
Benomyl is of such a low acute toxicity to mammals that it has been impossible or impractical to administer doses large enough to establish an LD50. It therefore has an arbitrary LD50 that is 'greater than 10,000 mg/kg/day for rats'. However, skin irritation may occur with workers exposed to benomyl(9). It is a mild to moderate eye irritant and is a skin sensitiser. Florists, mushroom pickers and flower growers have reported allergic reactions to benomyl(10).
    In 1992, benomyl exposure caused adverse occupational health effects (headaches, diarrhoea and sexual dysfunction) in agricultural workers in Florida(11).

Chronic toxicity
In a laboratory study, dogs fed benomyl in their diets for three months developed no major toxic effects but did show evidence of altered liver function at the highest dose (150 mg/kg). With longer exposure, more severe liver damage occurred including cirrhosis after two years(12).

Carcinogenic effects
The US Environmental Protection Agency classified benomyl as a possible human carcinogen(13). There is an element of doubt in this classification because carcinogenic studies have produced conflicting results. A two year experimental mouse study has shown it probably caused an increase in liver tumours. The Ministry of Agriculture Fisheries and Food (MAFF) takes the view that this was bought about by the hepatoxic effect of benomyl(14).

Reproductive effects
Tests on laboratory animals have shown benomyl can have an effect on reproduction. In one rat study, where the mothers were fed 1,000 mg/kg/day for four months, the offspring showed a decrease in viability and fertility(15). In studies to investigate the effects of benomyl on male reproductive performance, fertility was reduced at all dose levels tested. In another study a no-effect level of 15mg/kg/day was established based on testicular abnormalities(16).
    Permanent reductions occurred in the size of testes and male accessory glands in 100 day-old offspring from female laboratory rats receiving 31.2 mg benomyl/kg body weight per day. Rats developed a reduced sperm activity following acute inhalation exposure, acute and sub-chronic oral exposure. The same effect occurred in dogs following a single four hour inhalation exposure(17).

Eye defects
In 1993, the Observer, a UK national newspaper, published the first in a series of articles alleging a possible link between exposure of pregnant mothers to benomyl and their children being born without eyes (anophthalmia) or with related syndromes including reduced eyes and blindness due to severe damage of the optic stem(18). The newspaper cited a number of suspected clusters in the UK that may have corresponded to areas of benomyl use.
    Government officials at MAFF made an assessment of the claims but concluded it was doubtful there was a link. They said likely benomyl exposure in the pregnant mothers was not sufficiently high to cause developmental eye problems in their children. MAFF concluded: "The no effect level for teratogenicity based on all the available data was 30mg/kg/day. The exposure of both operators and consumers is several orders of magnitude lower than this no-effect level. It is therefore difficult to see how any link can be made with eye defects and exposure to benomyl."(19) 
    Studies have shown that eye defects can occur at relatively high doses. A test in which rats were dosed orally demonstrated evidence of microphthalmia at dose levels of 62.5 mg/kg and above(20).
    At the height of concern over benomyl, councillors on Lincoln's Environmental Committee urged local farmers to adopt a voluntary ban on the use of benomyl.
    In 1996 a Miami jury awarded US$4 million to a child whose mother was exposed in pregnancy to Benlate. The child was born without eyes. The mother in this case was subject to an unusually high dose of Benlate. The case is on appeal by the manufacturers. An important issue in the case is whether the timing of exposure - during the formation of the optic nerve in the foetus - is critical as well as the magnitude of exposure. A Benlate compensation case involving an English boy from Essex born without eyes is also due to be heard shortly in the US(21).

Mutagenic effects
There are conflicting negative and positive results making it difficult to form a definite conclusion relating to mutagenicity. Two papers show that benomyl causes an increased incidence of chromosomal aberrations. In a range of in vitro assays there was evidence that benomyl caused aneuploidy (a chromosome abnormality). Other results show it is not mutagenic(22).

Environment
Benomyl binds strongly to soil and does not dissolve in water to any great extent. When applied to turf, it has a half-life of three to six months, and when applied to bare soil the half-life is six to 12 months(23).

Resistance
Resistance to benzimidazole fungicides in general has reduced the market share of benomyl in recent years. Benomyl was the first truly systemic fungicide and originally showed a wide range of activity against pathogens in many different crops(24).

Crop damage claims in Florida
In 1991, many US growers blamed Benlate DF for destroying millions of dollars worth of crops. Growers placed as many as 1,900 damage claims against the manufacturers Du Pont, mostly involving ornamental crops in Florida. The reason for the crop damage is not clear. The Florida Department of Agriculture suggested Benlate was contaminated with dibutylurea and sulfonylurea herbicides. A non-pesticide theory suggested that unusual weather was also a contributory factor.
    After many years of legal wrangling Du Pont paid out about US$750 million in damages and out-of-court settlements. By 1993, a coalition of farm worker and environmental groups came together to form Benlate Victims Against Du Pont that called for a nation-wide boycott of Du Pont products.
    After carrying out tests, Du Pont denied that Benlate was contaminated with dibutylurea and sulfonylureas and stopped compensation pay-outs. In 1995, a Florida judge rejected a complaint from the Florida Department of Agriculture that had alleged such a link(25). The affair continues to inflict financial repercussions on Du Pont. The third quarter results in 1996 included a US$47 million charge relating to the Benlate recall(26).

Conclusion
The main area of concern with benomyl involves its chronic effects. At high doses, adverse effects such as eye birth defects occur after exposing experimental animals to the fungicide. MAFF says people are unlikely to receive such doses and therefore conclude it is safe. This issue raises two questions: is there a safe level of exposure, and is the timing of the exposure during pregnancy critical?
    As yet, national regulatory authorities have not taken a precautionary approach and banned benomyl on health grounds. An alternative, Azoxystrobin, may be coming onto the market. It is based on a natural fungicide and may prove to be safer than benomyl. However, it will probably be more expensive, and follows a chemical-for-chemical replacement strategy that may not be successful.

References
1. Tomlin, C., (Ed.) The Pesticide Manual, 10th Edition, British Crop Protection Council/Royal Society of Medicine, 1994.
2. Benomyl, Extoxnet, Pesticide Management Education Program, Cornell University, NY, May 1994.
3. World Health Organisation, WHO/PCS/94.87 Data sheet on benomyl, Geneva, 1994.
4. Whitehead, R (Ed) The UK Pesticide Guide, British Crop Protection Council/CAB International, 1996.
5. Thomas, M.R. and Garthwaite, D.G., Orchards and Fruit Stores in Great Britain 1992, Pesticide Usage Survey Report 115, Central Science Laboratory, 1994.
6. Thomas, M.R. and Garthwaite, D.G., Outdoor Bulbs and Flowers in Great Britain 1993, Pesticide Usage Survey Report 121, Central Science Laboratory, 1995.
7. Garthwaite, D.G., Thomas, M.R., Hart, M.J, and Wild, S, Outdoor vegetable crops in Great Britain 1995, Pesticide Usage Survey Report 134, Central Science Laboratory, 1997.
8. Thomas, M.R. and Garthwaite, D.G., Hardy Nursery Stock in Great Britain 1993, Pesticide Usage Survey Report 120, Central Science Laboratory, 1995.
9. Op. cit. 2.
10. Benomyl evaluation No. 57, MAFF, July 1992, pp109-111.
11. More problems for Benlate? Agrow, 13 March 1992, p13.
12. Op. cit. 2.
13. List of Chemicals Evaluated for Carcinogenic Potential, US EPA Office of Pesticide Programs, Washington, US, 1996.
14. Op. cit. 10, p91.
15. Benomyl, Environmental Health Criteria No 148, World Health Organisation, Geneva, Switzerland, 1993.
16. Op. cit. 10, p110.
17. Op. cit. 14.
18. Mystery of babies with no eyes, 'clusters' raise fears of link with pesticide, 17 January 1991.
19. Press statement on benomyl, MAFF, 1 March 1993.
20. OP. cit. 10, p110.
21. US$4 million for Benlate eye victim, Pesticides News No 33, p8.
22. Op. cit. 3.
23. Op. cit. 2.
24. Copping, L.G., Agrow's Top Twenty Five, PJB Publications, 1996, p105.
25. Various Agrow reports from March 1992 to June 1996.
26. Op. cit. 24.

[This article first appeared in Pesticides News No.35, March 1997, p20-21]