Monday, August 6, 2007

Agricultural Teratogens


According to the U.S. Environmental Protection Agency (EPA), a pesticide is "any substance or mixture of substances intended to prevent, destroy or repel any pest? Pests might include animals, plants, or microorganisms. All pesticides are potentially toxic to living organisms, otherwise they would be useless in the elimination of unwanted organisms.
Pesticide poisonings have been estimated by the World Health Organization to be as high as 3 million cases a year with possibly 220,000 deaths. There are a greater number of cases in developing countries as compared to industrialized regions.
The Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) was passed in 1947 by the U.S. Congress. This would group all pesticides under one law to be governed over by the U.S. Department of Agriculture (USDA). By 1972, FIFRA was reorganized and moved to the authority of the EPA. The new FIFRA with multiple amendments requires impact studies in toxicology and upon the environment as well as monitoring residue levels on foods.


Studies have determined insecticides (organochlorine insecticides) may interfere with fertility and reproduction by mimicking estrogen-like compounds. In some avian species, steroid metabolism is altered, making it impossible to transport calcium to the developing egg shell. This greatly decreases the strength of the shell and its resistance to pressures in the nest. A crack in the shell will result in bacterial infection and the resultant death of the embryo. Insecticides have also been found to accumulate and concentrate in the yolk sac of developing fish.
Rodent studies of DDT showed reduced testicular size in males and estrogenic effects in female rats. One isoform, o,p?isomer, has been shown to compete with estradiol for the estrogen binding site of receptors in rat uterine cytosol.
Other teratogenic insecticides include dieldrin (reduction in fertility, increased mortality, delayed ossification and increased supernumerary ribs) and Kepone (reduction in sperm count and reduced motility).


2,4,5-T has been blamed in the past for multiple birth defects such as cleft palate and renal abnormalities. However, it has been shown that it is not 2,4,5-T responsible for these malformations, but a contaminate 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD), found in 2,4,5-T when it isn manufactured correctly. Studies containing 30ug/g TCDD were used in 2,4,5-T teratologic studies resulting in cleft palate and congenital renal abnormalities. Greatly exaggerated doses of 2,4,5-T (15-100 mg/kg) during organogenesis have been shown to cause cleft palate and cystic kidney in some, but not all, tested species.


Organomercurials have been used as fungicides for many decades. They have been associated with many teratogenic events such as the epidemic in Minamata Bay, Japan (more information can be seen below).
The category of fungicides also include phthalimides and dithiocarbamates. Two phthalimides, captafol and folpet, are structurally similar to thalidomide. Therefore, great concern was raised in their testing laboratories regarding their potential teratogenicity. Studies in hamster did produce congenital malformations, however, studies in other animals failed to repeat these results (similar to the thalidomide experience). The dithiocarbamate, maneb, is associated with embryotoxicity as well as a decrease in litter number and pregnancy rate as well as alterations in estrous cycle and fetal development.

Congenital Minamata Disease

Methylmercury was used in the past as a fungicide on wheat and grains. Cases have been documented in Iraq (1971-1972), Sweden, Japan and New Mexico of birth defects due to maternal ingestion of bread made with contaminated grain. There have also been documented cases in Canada, New York and Sweden of paper mill contaminants polluting the water with inorganic mercury. This mercury is converted to the biologically active methylmercury by microbes that live on the bottom of the lakes. It is then concentrated in the flesh of fish. Here fetal damage may occur by maternal intake of fish and shellfish containing methylmercury. Exposure in utero may result in sensory and motor impairments, cerebral palsy, mental retardation and behavioral damage.
Methylmercury can easily pass through the placenta and into the fetus. Often the fetus is inefficient at excreting mercury, so it builds up and compounds the effect of the poisoning. The fetus is approximately 4-10 times more sensitive to methylmercury poisoning as compared to an adult. This situation can only be prevented by the elimination of methylmercury from our food supply.
Between 1953 and 1965 there were over a hundred adult men and women developing symptoms of central nervous system disorders such as ataxia, alterations in gait, tremors, altered sight and sensation. In 1955 in the Minamata Bay area of Kyushu, Japan, there was a large influx of cases of severe neurological disorders in newborn children. There were cases of cerebral palsy, some children were diplegic and others were tetraplegic. They were all mentally handicapped. Some villages had 6-12% of their newborns affected. Together, these disorders are now known as Congenital Minamata Syndrome. In 1959, it was found that methylmercury was being dumped into the bay by a plant of the Chisso Corporation.
It wasn until 1962 that conclusive evidence was published linking the dumping of methylmercury to these neurological birth defects. It was thought, to this point, that poisons couldn cross the placenta. Therefore, it took some time to confirm that an environmental pollutant could induce birth defects in humans. The link between these birth defects and methylmercury have been confirmed multiple times in animal studies.
Children with Congential Minamata Syndrome seem to be normal at birth and begin to present symptoms at approximately six months of age. They have instability of the neck, convulsions, reduced IQ, microcephaly, malformed limbs, restricted growth and an altered cerebellum. In utero exposure to methylmercury induces general brain atrophy and hypoplasia.

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