Misc Info on Round-up from Rex Warren

Subject: Misc Info on Round-up from Rex Warren
Date:     Wed, 29 May 2002 10:50:27 -0400
From:      Stephen Tvedten <steve@getipm.com>
Organization:     Get Set Inc. (www.getipm.com)

To: Paul Helliker <phelliker@cdpr.ca.gov>
Director, State of California, Department of Pesticide Regulation

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RoundUp--Lymphoma Connection
From: Sadhbh O' Neill of “Genetic Concern.”

PRESS RELEASE - 22 JUNE - New Study Links Monsanto's Roundup to Cancer
A recent study by eminent oncologists Dr. Lennart Hardell and Dr. Mikael Eriksson of Sweden [1], has revealed clear links between one of the world's biggest selling herbicide, glyphosate, to non-Hodgkin's lymphoma, a form of cancer [2].

In the study published in the 15 March 1999 Journal of American Cancer Society, the researchers also maintain that exposure to glyphosate 'yielded increased risks for NHL.' They stress that with the rapidly increasing use of glyphosate since the time the study was carried out, 'glyphosate deserves further epidemiologic studies.'

Glyphosate, commonly known as Roundup, is the world's most widely used herbicide. It is estimated that for 1998, over a 112,000 tonnes of glyphosate was used world-wide. It indiscriminately kills off a wide variety of weeds after application and is primarily used to control annual and perennial plants.

71% of genetically engineered crops planted in 1998 are designed to be resistant to herbicides such as glyphosate, marketed by Monsanto as Roundup. Companies developing herbicide resistant crops are also increasing their production capacity for the herbicides such as glyphosate, and also requesting permits for higher residues of these chemicals in genetically engineered food. For example, Monsanto have already received permits for a threefold increase in herbicide residues on genetically engineered soybeans in Europe and the U.S., up from 6 parts per million (PPM) to 20 PPM.

According to Sadhbh O' Neill of Genetic Concern, 'this study reinforces concerns by environmentalists and health professionals that far from reducing herbicide use, glyphosate resistant crops may result in increased residues to which we as consumers will be exposed in our food.'

'Increased residues of glyphosate and its metabolites are already on sale via genetically engineered soya, common in processed foods. However no studies of the effects of GE soya sprayed with Roundup on health have been carried out either on animals or humans to date,' she continued.

The United States Department of Agriculture (USDA) statistics from 1997 show that expanded plantings of Roundup Ready soybeans (i.e. soybeans genetically engineered to be tolerant to the herbicide) resulted in a 72% increase in the use of glyphosate. According to the Pesticides Action Network, scientists estimate that plants genetically engineered to be herbicide resistant will actually triple the amount of herbicides used. Farmers, knowing that their crop can tolerate or resist being killed off by the herbicides, will tend to use them more liberally.

O' Neill concluded: 'The EPA when authorising Monsanto's field trials for Roundup-ready sugar beet did not consider the issue of glyphosate. They considered this to be the remit of the Pesticides Control Service of the Department of Agriculture. Thus nobody has included the effects of increasing the use of glyphosate in the risk/benefit analysis carried out. It is yet another example of how regulatory authorities supposedly protecting public health have failed to implement the 'precautionary principle' with respect to GMOs.'

ENDS
Further information: Sadhbh O' Neill at 01-4760360 or 087-2258599 or (home) 01-6774052

Notes
[1] Lennart Hardell, M.D., PhD. Department of Oncology, Orebro Medical Centre, Orebro, Sweden and Miikael Eriksson, M.D., PhD, Department of Oncology, University Hospital, Lund, Sweden, 'A Case-Control Study of Non-Hodgkin Lymphoma and Exposure to Pesticides', Cancer, March 15, 1999/ Volume 85/ Number 6.

The findings are based on a population-based case-control study conducted in Sweden between 1987 - 1990. The necessary data was ascertained by a series of comprehensive questionnaires and follow-up telephone interviews. Dr. Hardell and Dr. Eriksson found that 'exposure to herbicides and fungicides resulted in significantly increased risks for NHL'.

[2] Lymphoma is a form of cancer that afflicts the lymphatic system. It can occur at virtually any part of the body but the initial symptoms are usually seen as swellings around the lymph nodes at the base of the neck. There are basically two main kinds of lymphoma, i.e. Hodgkin's disease and non-Hodgkin's lymphoma.

The incidence of NHL has increased rapidly in most Western countries over the last few decades. According to the American Cancer Society, there has been an alarming 80% increase in incidences of NHL since the early 1970's.

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Ingestion of RoundUp has been shown to cause "irritation of the oral mucous membrane and gastrointestinal tract…pulmonary dysfunction, oliguria, metabolic acidosis, hypotension, leukocytosis and fever." Monsanto's own toxicologist, Rebecca Tominack, participated in this study.(Tominack RL, Yang GY, Tsai WJ, Chung HM, Deng JF, 1991. Taiwan National Poison Center survey of glyphosate-surfactant herbicide ingestions. J Toxicol Clin Toxicol 1991; 29 (1): 91-109)Many people report experiencing severe digestive problems related to irritation of their gastrointestinal tract after overexposure to RoundUp, limiting the foods their bodies will tolerate to a very few bland foods.This is believed to be related to the fact that in a 1983 study by Heitanen, Linnainmaa and Vainio, RoundUp's main ingredient, glyphosate, was shown to decrease the hepatic level level of cytochrom P-450, monooxygenase activities, and the intestinal activity of aryl hydrocarbon hydroxylase.The inhibition of erythrocyte glutathione conjugate transport by polyethoxylated surfactants has also been reported in a 1993 letter to FEBS from studies done by P. G. Board, part of the Molecular Genetics Group, John Curtin School of Medical Research, Australian National University, Canberra.Glutathione is a tripeptide which the body produces from the amino acids cysteine, glutamic acid, and glycine. Glutathione is a powerful antioxidant produced in the liver, where it detoxifies harmful compounds so that they can be excreted through the bile. The glutathione released from the liver directly into the bloodstream helps to maintain the integrity of red blood cells and protect white blood cells. Glutathione is also found in the lungs. In the intestinal tract, it is needed for carbohydrate metabolism, and also appears to exert anti-aging effects, aiding in the breakdown of oxidized fats that may contribute to atherosclerosis. Glutathione's role in carbohydrate metabolism is compromised by the effect of RoundUp's surfactant, POEA, on erythrocyte glutathion conjugate transport.RoundUp causes damage to the liver that inhibits the liver's ability to process toxic substances.Research subject animals injected with glyphosate evidenced a depressed function of the liver. "Glyphosate decreased the hepatic function of cytochrome P-450 and monoxygnease activities and the intestinal activity of aryl hydrocarbon hydrolase." (Heitanen et al, 1983). The P-450 enzyme system is one of the main body systems for detoxifying harmful chemicals. When it becomes impaired by those same chemicals it is supposed to be detoxifying, the effects of a given chemical on the body increase dramatically.(Heitanen, et al., 1983. Effects of phenoxyherbicides and glyphosate on the hepatic and intestinal biotransformation activities in the rat. Acta Pharmacol Toxicol (Copenh) 1983 Aug; 53(2):103-12.)Testing of patients suffering RoundUp overexposure has indicated damage to their P-450 enzyme system.Roundup produces significant increases in sister-chromatid exchanges (SCE), albeit in higher concentrations over those used for other pesticides. This suggests that it should be evaluated in other genetic tests measuring mutations and chromosome aberrations, although few studies of this nature have yet been done.A 1980 study by Vigfusson and Vyse noted sister-chromatid exchanges in human lymphocytes in vitro. This lymphocyte disturbance correlates with the swelling experienced by persons poisoned by RoundUp.(Vigfusson, N.V. and Vyse, E.R. (1980), "The effect of the pesticides, Dexon, Captan, and Roundup, on sister-chromatid exchanges in human lymphocytes in vitro". MUTATION RESEARCH, v.79 p.53-57.)William Meggs, M.D., Ph.D., School of Medicine, East Carolina University:In patients who have been chemically injured, Meggs has noted significant lymphatic hyperplasia, lymphatic tissue that is swollen and engorged. He has also found significant cobblestoning in upper airway passages. This represents chronic inflammation caused by lymphocytes migrating out of the blood stream and seeping into the tissues. Meggs has also noted thickening of the structure called the basement membrane, the structure on which the lining of cells that lines the interior of the nose sits. Meggs' study also found a defect in the tight junctions (the joining of cells together) and a proliferation of nerve fibers."Chemicals bind to receptors on nerve fibers and produce something called neurogenic inflammation. These chemicals bind to these receptors and cause the release of potent substances that produce inflammation in tissue.When chemicals bind to nerve fibers, they can produce inflammation. Inflammation, in turn, produces other changes in the tissue, and it brings in these lymphocytes. We believe that inflammation causes these barrier cells to open up and sometimes even come off the basement membrane. Below the basement membrane is the nerve fibers, so we have a process whereby a chemical exposure will damage the lining of the nose. What happens is people have a large chemical exposure, they breathe in noxious chemicals, and this damages the epithelium. This huge exposure is able to penetrate this barrier we have between the chemicals we breathe in and these nerve cells beneath the lining layer that react to chemicals by producing inflammation. The inflammation, in turn, produces substances that cause further damage to the lining cell, and actually produce the substances which cause the tight junctions between these cells to open up. In some cases the cells actually come off and just leave these bare nerves exposed. Once you have the bare nerves exposed, low levels of chemicals that we all experience every day are enough to produce inflammation which in turn keeps the epithelium damaged."RoundUp was found to cause significant DNA damage to erythrocytes (red blood cells) in a study done in 1997 by Clements, Ralph and Petras. RoundUp's surfactant, POEA, is known to cause haemolysis.(Clements C, Ralph S, Pertas M, 1997. Genotoxicity of select herbicides in Rana catesbeiana tadpoles using the alkaline single-cell gel DNA electrophoresis (comet) assay. Environ Mol Mutagen 1997; 29(3):277-288.)(Sawada Y, Nagai Y, Ueyama M, Yamamoto I, 1988. Probable toxicity of surface-active agent in commercial herbicide containing glyphosate. Lancet. 1988 Feb 6;1(8580):299.)In haemolysis, hemoglobin leaks from the red blood cells, leaving them unable to transport sufficient supplies of oxygen to the body's tissues.The chest pains, difficulty breathing, and impaired cognitive skills reported by persons who have sustained RoundUp poisoning also point to impairment of the blood's oxygen transport system, hemoglobin, as being responsible for these symptoms. This impairment of the erythrocytes' ability to deliver adequate oxygen to both brain and body results in impaired tissue perfusion and hypoxia."The brain is particularly vulnerable to hypoxia, and exposure to toxins that interfere with the intake, transport and utilization of oxygen provoke rapid and major neuronal damage. Compounds crossing the blood-brain barrier may induce both general and extremely localized neurotoxic effects."(Kyvik KR, Morn BE, 1995. Environmental poisons and the nervous system. Tidsskr Nor Laegeforen 1995. June 10; 115(15):1834-8.)According to both the EPA and the World Health Organization in 1993 and 1994, glyphosate appears to mimic adrenaline. This would explain the sleeping problems encountered by many persons exposed to RoundUp, as for them, cortisol appears to no longer be properly regulated by their bodies' adrenal glands.(US EPA, 1993. EPA Reregistration Eligibility Document, Glyphosate, Office of Prevention, Pesticides and Toxic Substances, Washington, D.C., September 1993.)(IPCS, 1994. Environmental health criteria 159: Glyphosate. International Programme of Chemical Safety, World Health Organization, Geneva.)

Ingestion of RoundUp has been shown to cause "irritation of the oral mucous membrane and gastrointestinal tract…pulmonary dysfunction, oliguria, metabolic acidosis, hypotension, leukocytosis and fever."

(Tominack RL, Yang GY, Tsai WJ, Chung HM, Deng JF, 1991. Taiwan National Poison Center survey of glyphosate-surfactant herbicide ingestions. J Toxicol Clin Toxicol 1991; 29 (1): 91-109)

Many people report experiencing severe digestive problems related to irritation of their gastrointestinal tract after overexposure to RoundUp, limiting the foods their bodies will tolerate to a very few bland foods.

This is believed to be related to the fact that in a 1983 study by Heitanen, Linnainmaa and Vainio, RoundUp's main ingredient, glyphosate, was shown to decrease the hepatic level level of cytochrom P-450, monooxygenase activities, and the intestinal activity of aryl hydrocarbon hydroxylase.

The inhibition of erythrocyte glutathione conjugate transport by polyethoxylated surfactants has also been reported in a 1993 letter to FEBS from studies done by P. G. Board, part of the Molecular Genetics Group, John Curtin School of Medical Research, Australian National University, Canberra.

Glutathione is a tripeptide which the body produces from the amino acids cysteine, glutamic acid, and glycine. Glutathione is a powerful antioxidant produced in the liver, where it detoxifies harmful compounds so that they can be excreted through the bile. The glutathione released from the liver directly into the bloodstream helps to maintain the integrity of red blood cells and protect white blood cells. Glutathione is also found in the lungs. In the intestinal tract, it is needed for carbohydrate metabolism, and also appears to exert anti-aging effects, aiding in the breakdown of oxidized fats that may contribute to atherosclerosis. Glutathione's role in carbohydrate metabolism is compromised by the effect of RoundUp's surfactant, POEA, on erythrocyte glutathion conjugate transport.

RoundUp causes damage to the liver that inhibits the liver's ability to process toxic substances.

Research subject animals injected with glyphosate evidenced a depressed function of the liver. "Glyphosate decreased the hepatic function of cytochrome P-450 and monoxygnease activities and the intestinal activity of aryl hydrocarbon hydrolase." (Heitanen et al, 1983). The P-450 enzyme system is one of the main body systems for detoxifying harmful chemicals. When it becomes impaired by those same chemicals it is supposed to be detoxifying, the effects of a given chemical on the body increase dramatically.

(Heitanen, et al., 1983. Effects of phenoxyherbicides and glyphosate on the hepatic and intestinal biotransformation activities in the rat. Acta Pharmacol Toxicol (Copenh) 1983 Aug; 53(2):103-12.)

Testing of patients suffering RoundUp overexposure has indicated damage to their P-450 enzyme system.

Roundup produces significant increases in sister-chromatid exchanges (SCE), albeit in higher concentrations over those used for other pesticides. This suggests that it should be evaluated in other genetic tests measuring mutations and chromosome aberrations, although few studies of this nature have yet been done.

A 1980 study by Vigfusson and Vyse noted sister-chromatid exchanges in human lymphocytes in vitro. This lymphocyte disturbance correlates with the swelling experienced by persons poisoned by RoundUp.

(Vigfusson, N.V. and Vyse, E.R. (1980), "The effect of the pesticides, Dexon, Captan, and Roundup, on sister-chromatid exchanges in human lymphocytes in vitro". MUTATION RESEARCH, v.79 p.53-57.)

In patients who have been chemically injured, Meggs has noted significant lymphatic hyperplasia, lymphatic tissue that is swollen and engorged. He has also found significant cobblestoning in upper airway passages. This represents chronic inflammation caused by lymphocytes migrating out of the blood stream and seeping into the tissues. Meggs has also noted thickening of the structure called the basement membrane, the structure on which the lining of cells that lines the interior of the nose sits. Meggs' study also found a defect in the tight junctions (the joining of cells together) and a proliferation of nerve fibers.

"Chemicals bind to receptors on nerve fibers and produce something called neurogenic inflammation. These chemicals bind to these receptors and cause the release of potent substances that produce inflammation in tissue.

When chemicals bind to nerve fibers, they can produce inflammation. Inflammation, in turn, produces other changes in the tissue, and it brings in these lymphocytes. We believe that inflammation causes these barrier cells to open up and sometimes even come off the basement membrane. Below the basement membrane is the nerve fibers, so we have a process whereby a chemical exposure will damage the lining of the nose.

What happens is people have a large chemical exposure, they breathe in noxious chemicals, and this damages the epithelium. This huge exposure is able to penetrate this barrier we have between the chemicals we breathe in and these nerve cells beneath the lining layer that react to chemicals by producing inflammation. The inflammation, in turn, produces substances that cause further damage to the lining cell, and actually produce the substances which cause the tight junctions between these cells to open up. In some cases the cells actually come off and just leave these bare nerves exposed. Once you have the bare nerves exposed, low levels of chemicals that we all experience every day are enough to produce inflammation which in turn keeps the epithelium damaged."

RoundUp was found to cause significant DNA damage to erythrocytes (red blood cells) in a study done in 1997 by Clements, Ralph and Petras. RoundUp's surfactant, POEA, is known to cause haemolysis.

(Clements C, Ralph S, Pertas M, 1997. Genotoxicity of select herbicides in Rana catesbeiana tadpoles using the alkaline single-cell gel DNA electrophoresis (comet) assay. Environ Mol Mutagen 1997; 29(3):277-288.)

(Sawada Y, Nagai Y, Ueyama M, Yamamoto I, 1988. Probable toxicity of surface-active agent in commercial herbicide containing glyphosate. Lancet. 1988 Feb 6;1(8580):299.)

In haemolysis, hemoglobin leaks from the red blood cells, leaving them unable to transport sufficient supplies of oxygen to the body's tissues.

The chest pains, difficulty breathing, and impaired cognitive skills reported by persons who have sustained RoundUp poisoning also point to impairment of the blood's oxygen transport system, hemoglobin, as being responsible for these symptoms. This impairment of the erythrocytes' ability to deliver adequate oxygen to both brain and body results in impaired tissue perfusion and hypoxia.

"The brain is particularly vulnerable to hypoxia, and exposure to toxins that interfere with the intake, transport and utilization of oxygen provoke rapid and major neuronal damage. Compounds crossing the blood-brain barrier may induce both general and extremely localized neurotoxic effects."

(Kyvik KR, Morn BE, 1995. Environmental poisons and the nervous system. Tidsskr Nor Laegeforen 1995. June 10; 115(15):1834-8.)

According to both the EPA and the World Health Organization in 1993 and 1994, glyphosate appears to mimic adrenaline. This would explain the sleeping problems encountered by many persons exposed to RoundUp, as for them, cortisol appears to no longer be properly regulated by their bodies' adrenal glands.

(US EPA, 1993. EPA Reregistration Eligibility Document, Glyphosate, Office of Prevention, Pesticides and Toxic Substances, Washington, D.C., September 1993.)

(IPCS, 1994. Environmental health criteria 159: Glyphosate. International Programme of Chemical Safety, World Health Organization, Geneva.)

Monsanto states that glyphosate is not a cholinesterase inhibitor. The MSDS on RoundUp also says that glyphosate is not a cholinesterase inhibitor. Yet, glyphosate is a an organophosphorus, and the "toxic effects of organophosphorus (OP) compounds are predicated on their irreversible inhibition of acetylcholinesterase (AchE) and other serine hydrolases."

(Viragh C, Kovach IM, Pannell L, 1999. Small Molecular Products of Dealkylation in Soman-Inhibited Electric Eel Acetylcholinesterase. American Chemical Society, June 11, 1999.)

Merely saying glyohosate is not a cholinesterase inhibitor, however, does not define whether RoundUp itself in full formulation is a cholinesterase inhibitor, and there are no published studies that purport to answer this question.

In 1988, Yusuke Sawada, et al. did a study in which they concluded that the surfactant in RoundUp (POEA) is more toxic than RoundUp's main ingredient, glyphosate. A study by Servizi et al in 1987 found that POEA is two to three times more toxic than glyphosate, and that the synergy of the two ingredients may even be more acutely toxic than the two ingredients combined.

The answer to whether RoundUp in full formulation is a cholinesterase inhibitor can only be determined by looking at anecdotal evidence. Many doctors, however, based on Monsanto's advertising that glyphosate is not a cholinesterase inhibitor, refuse to test RoundUp poisoning victims for cholinesterase inhibition, so even anecdotal evidence is not readily available.

(Sawada Y, Nagai Y, Ueyama M, Yamamoto I, 1988. Probable toxicity of surface-active agent in commercial herbicide containing glyphosate. Lancet. 1988 Feb 6;1(8580):299.)

(Servizi JA, Gordon RW, Martens DW, 1987. Acute toxicity of Garlon 4 and Roundup herbicides to salmon, Daphnia, and trout.
Bull Environ Contam Toxicol. 1987 Jul;39(1):15-22. )

An October 27, 1999 article by PANUPS (Pesticide Action Network Updates Service) offers the information that according to a European Community report on glyphosate (not released at that time), glyphosate poses a significant risk to certain beneficial insects.

In a 1993 article on organophosphate poisoning, British researcher, T. C. Marrs, indicated that "certain OPs are exploited for their anticholinesterase effects, including defoliants such as 'DEF', herbicides such as glyphosate." The article goes on to say that the cholinergic syndrome is "caused by acetylcholinesterase inhibition."

(Marrs, TC, 1993. Organophosphate poisoning. Pharmacol Ther 1993; 58(1): 51-66.)

An area that has yet to be explored is the impact of the degradation process for glyphosate on the serine cycle. The serine cycle plays a strong part in cholinesterase inhibition in humans. From available research, it is easy to conclude that, while glyphosate itself might not technically be anticholinergic, the degradants of glyphosate might very well be cholinesterase inhibitors.

Glyphosate's degradation pathway shows that, depending one which soil organisms are present, glyphosate degrades into sarcosine, formaldehyde, AMPA, and Methylamine.

Formaldehyde is not only carcinogenic, but impairs the serine cycle, an important part of the human metabolic process. According to a document on the ESTHER database, "cholinesterases are readily phosphorylated at the active site serine by a variety of organophosphorus agents (OP) and carbamates."

(Goldberg I, Mateles RI , 1975. Growth of Pseudomonas C on C1 compounds: enzyme activities in extracts of Pseudomonas C cells grown on methanol, formaldehyde, and formate as sole carbon sources. J Bacteriol 1975 Apr;122(1):47-53)

There is reported evidence of a patient who, after exposures to RoundUp, showed a depressed pseudocholinesterase. SmithKline Beecham's Normal Values reference range is 3200 - 6600. On 6/4/96, after three major exposures to RoundUp, this patient's pseudocholinesterase was 2887. On 7/8/96, after an additional major exposure to RoundUp, this patient's pseudocholinesterase was 2700. The last reading during the period of this patient's exposures to RoundUp was 2733 on 8/7/96. Only with the assistance of successful drug therapy (large doses of dextromethorophan) was this reading reversed to 3586 on 10/22/96.

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PANUPS: Monsanto Agrees to Change Ads and EPA Fines Northrup King. January 10, 1997.

Monsanto Agrees to Change Ads and EPA Fines Northrup King Monsanto Co. agreed to change its advertising for glyphosate-based products, including Roundup, in response to complaints by the New York Attorney General's office that the ads were misleading. Based on their investigation, the Attorney General's office felt that the advertising inaccurately portrayed Monsanto's glyphosate-containing products as safe and as not causing any harmful effects to people or the environment. According to the state, the ads also implied that the risks of products such as Roundup are the same as those of the active ingredient, glyphosate, and do not take into account the possible risks associated with the product's inert ingredients.

As part of the agreement, Monsanto will discontinue the use of terms such as "biodegradable" and "environmentally friendly" in all advertising of glyphosate-containing products in New York state and will pay $50,000 toward the state's costs of pursuing the case. The Attorney General has been challenging the ads since 1991.

Monsanto maintains that it did not violate any federal, state or local law and that its claims were "true and not misleading in any way." The company states that they entered into the agreement for settlement purposes only in order to avoid costly litigation.

According to a 1993 report published by the School of Public Health at the University of California, Berkeley, glyphosate was the third most commonly-reported cause of pesticide illness among agricultural workers. Another study from the School of Public Health found that glyphosate was the most commonly reported cause of pesticide illness among landscape maintenance workers. (Both studies were based on data collected between 1984 and 1990.)

In the first nine months of 1996, Monsanto's worldwide agrochemical sales increased by 21% to US$2.48 billion, due largely to increased sales of Roundup.

Also in November 1996, Northrup King Co. agreed to pay a US$165,200 fine to the U.S. Environmental Protection Agency (EPA) for importing, producing, selling and distributing an unregistered pesticide P genetically engineered corn containing Bacillus thurgiensis (Bt). This was EPA's first legal action involving a genetically engineered plant pesticide.

According to EPA, the company's activities violated the U.S. Federal Insecticide, Fungicide and Rodenticide Act and included failing to file with EPA the required paperwork for importing the Bt corn, and producing the pesticide at eight unregistered facilities during 1994-95.

Northrup King, a Sandoz Seeds subsidiary based in Minnesota, maintains that they had been working with the EPA to obtain registration for their Bt corn and expected approval last spring. However, in order to have as much seed as possible to sell to U.S. growers, the company shipped seed to Chile for winter production and brought the increased volumes back to the U.S. for packaging and sale. A company spokesperson stated that the federal process took longer than expected, and therefore Northrup King was in "technical violation" by letting its production get ahead of registration. The originally proposed fine of US$208,500 was reduced by 20% because of what EPA officials called the company's "cooperation and good faith efforts to come into compliance."

Northrup King's Bt corn, developed in collaboration with Monsanto using its Yieldgard technology, was registered on August 5, 1996, and the company has been selling seed to U.S. farmers since then for next season's plantings. According to reports, the company expected to sell out by the end of the 1996, and is projecting 500,000 to one million acres planted with the company's seed by next spring.

Sources: Agrow: World Crop Protection News, November 15, November 29 & December 13, 1996; EPA News Release, Region 5, November 4, 1996; Minneapolis Star Tribune, November 7, 1996; The Gene Exchange, December 1996; Preventing Pesticide-related Illness in California Agriculture, William Pease, et al., 1993; Pesticides in the Home and Community: Health risks and policy alternatives, J.C. Robinson et al., 1994.

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Roundup Inhibits Steroidogenesis by Disrupting Steroidogenic Acute Regulatory (StAR) Protein Expression
Lance P. Walsh,1 Chad McCormick,1 Clyde Martin,2 and Douglas M. Stocco1

1Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, Texas, USA 2Department of Mathematics, Texas Tech University, Lubbock, Texas, USA

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Abstract Recent reports demonstrate that many currently used pesticides have the capacity to disrupt reproductive function in animals. Although this reproductive dysfunction is typically characterized by alterations in serum steroid hormone levels, disruptions in spermatogenesis, and loss of fertility, the mechanisms involved in pesticide-induced infertility remain unclear. Because testicular Leydig cells play a crucial role in male reproductive function by producing testosterone, we used the mouse MA-10 Leydig tumor cell line to study the molecular events involved in pesticide-induced alterations in steroid hormone biosynthesis. We previously showed that the organochlorine insecticide lindane and the organophosphate insecticide Dimethoate directly inhibit steroidogenesis in Leydig cells by disrupting expression of the steroidogenic acute regulatory (StAR) protein. StAR protein mediates the rate-limiting and acutely regulated step in steroidogenesis, the transfer of cholesterol from the outer to the inner mitochondrial membrane where the cytochrome P450 side chain cleavage (P450scc) enzyme initiates the synthesis of all steroid hormones. In the present study, we screened eight currently used pesticide formulations for their ability to inhibit steroidogenesis, concentrating on their effects on StAR expression in MA-10 cells. In addition, we determined the effects of these compounds on the levels and activities of the P450scc enzyme (which converts cholesterol to pregnenolone) and the 3ß-hydroxysteroid dehydrogenase (3ß-HSD) enzyme (which converts pregnenolone to progesterone). Of the pesticides screened, only the pesticide Roundup inhibited dibutyryl [(Bu)2]cAMP-stimulated progesterone production in MA-10 cells without causing cellular toxicity. Roundup inhibited steroidogenesis by disrupting StAR protein expression, further demonstrating the susceptibility of StAR to environmental pollutants. Key words: chemical mixtures, cytochrome P450 side chain cleavage, environmental endocrine disruptor, 3ß-hydroxysteroid dehydrogenase, Leydig cells, Roundup, steroid hormones, steroidogenesis, steroidogenic acute regulatory protein. Environ Health Perspect 108:769-776 (2000). [Online 12 July 2000]
http://ehpnet1.niehs.nih.gov/docs/2000/108p769-776walsh/abstract.html

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Address correspondence to D.M. Stocco, Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX 79409 USA. Telephone: (806) 743-2505. Fax: (806) 743-2990. E-mail: doug.stocco@ttmc.ttuhsc.edu We thank D. Alberts for technical assistance.

This work was supported by NIH grant HD17481 to D. Stucco. L. Walsh was supported by NIH grant T32-HD07271 and a scholarship from the Lubbock Achievement Awards for College Scientists Chapter.

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