Bug Spray Worse Than the Bite?
It may be healthier to endure pesky bug bites rather than don insect repellant, according to New York state officials. The state placed a ban on insect repellants containing concentrations of more than 30% diethyltoluamide, or DEET. Large doses of DEET have been linked to skin blisters, seizures, and deaths of several children.
Chemical manufacturers are protesting the decision because they believe the links are largely based on anecdotal evidence. DEET effectively wards off mosquitoes and ticks and is the world's most popular insect repellant, according to the Chemical Specialties Manufacturers Association, which represents 440 chemical companies.
The ban, proposed in 1992 by the New York State Department of Health's environmental health division, has not taken effect yet because it is still being battled out in the courts. In 1989, New York and other northeastern states began warning consumers not to use insect repellants with high concentrations of DEET and to be particularly sparing when applying the repellants to children. In 1992, New York issued the ban on repellants containing more than 30% DEET, but the CSMA prevented the ban from going into effect by obtaining a restraining order. A state appeals court ruled in favor of the department this past spring, but the CSMA was able to obtain another restraining order while attempting to appeal the decision again.
The ban was based "on a risk benefit analysis of reports of adverse reactions and tests of the efficacy of DEET," said James Leach, a research scientist with the New York State Department of Health's Bureau of Toxic Substance Assessment. There are few completed scientific studies on the health effects of DEET. There are, however, documented cases of adverse reactions in the scientific literature. In addition, the annual reports of the American Association of Poison Control Centers Toxic Exposure Surveillance System show calls concerning insect repellants have increased into the thousands in the last several years. Although the reports do not break down the calls concerning DEET specifically, according to Leach, DEET is the active ingredient in the overwhelming majority of insect repellants.
The EPA is awaiting the results of several studies before evaluating the status of DEET. "There are many studies being conducted that have not been resolved yet," said Whang Phang, a toxicologist with EPA's Office of Pesticides. "There are a lot of questions that need to be resolved."
Phang indicated that the anecdotes concerning the adverse health effects of DEET may be due to misapplication of the insect repellants. "With the increase in Lyme diseases in the north, people use a lot of DEET," he said. "How one applies [the insect repellants] is important." Leach said it is unclear whether DEET is effective in repelling deer ticks.
Several manufacturers of DEET undertook a study in 1992 on the health effects of the chemical and concluded that it was safe to use as an active ingredient in insect repellants. The study included evaluations of acute, subchronic, and chronic toxicity, oncogenicity, teratology, neurotoxicity, mutagenicity, pharmacokinetics, and human dermal absorption.
The study concluded that the only adverse effects on human health are a low potential to produce systemic toxicity or to cause skin sensitization, and the potential to cause eye or skin irritation in humans. The animal research indicated that DEET does not have the potential to cause cancer, nor cause birth defects, according to the writers of the study.
Healthy male volunteers were used in the human dermal absorption tests, which indicated that less than 10% of the administered DEET was absorbed following dermal administration.
Because they deem DEET as safe, the chemical manufacturers aim to keep insect repellants with high concentrations of DEET on the market. But there have been concerns raised about whether concentrations over 30% actually ward off more insects. New York state officials do not think so. "We examined the data and found no clear incremental benefit with concentrations over 30%," said Frank Hegener, an associate chemist with the pesticide product registration section in the state Department of Environmental Conservation. "Concentrations below 30% appeared to have the same effects as concentrations over 30%."
If the ban survives the appeal, it will affect many products, including Repel Insect Repellant, Ole Time Woodman Jungle Formula, Cutter Formula 100 Maximum Strength, Maximum Protection Off, Maximum Strength Deep Woods Off, Jungle Plus, Ben's 100 Insect Repellant, Muskol Insect Repellant, and Skeeter Stop 100.
Ambivalent Antihistamines
Warding off allergies with antihistamines may prove to be dangerous for allergy sufferers, if recent studies on mice are any indication. The study found that three widely used antihistamines stimulate tumor growth in mice.
Lorne Brandes and colleagues at the Manitoba Institute of Cell Biology at the University of Manitoba in Winnipeg, Canada, injected tumor culture lines into mice and then administered antihistamines daily in varying estimated human-equivalent doses for 18-21 days. The researchers then sacrificed the mice and surgically removed the tumors. In comparing the weights of the tumors, they found that three of the five antihistamines tested caused the tumors to grow heavier. This innovative method differs from traditional tests for carcinogenicity, which involve administering a substance to healthy laboratory animals; as a result, the study's conclusions are being questioned.
The three antihistamines that were found to cause the existing tumors in the mice to grow larger are loratadine, which is used in Claritin, made by Schering-Plough of Madison, New Jersey; astemizole, the main ingredient in Hismanal, made by Janssen Pharmaceutica Inc. of Titusville, New Jersey; and hydroxyzine, used in Atarax, made by the Roerig Division of Pfizer Inc. of New York. Following the publication of the study, the manufacturers of these drugs issued statements defending their products and criticizing the researchers' human risk assessment methods.
The two other drugs tested in the study were cetrizine, which is used in Reactine, also made by Pfizer, and doxylamine, used in over-the-counter drugs such as NyQuil and Unisom, which were not found to stimulate tumor growth.
The researchers defend their methods in the report of the study, saying, "Although the potential for carcinogenicity has received considerable attention in preclinical drug testing in rodents, the propensity of pharmaceuticals to enhance the growth of existing tumors or the development of malignancy induced by chemical or viral initiators has been neglected."
The study was published in the 18 May 1994 issue of the
Journal of the National Cancer Institute
along with an editorial written by Douglas L. Weed, of the Preventive Oncology Branch, Division of Cancer Prevention and Control, of the National Cancer Institute. Weed raised questions about the human risk assessment methods that were involved in the study and called for further research, recommending that no immediate changes be made in the use of the antihistamines.
Brandes had called on the Food and Drug Administration to change the labeling on the antihistamines, but the FDA said such a move would be premature. In a press release, the agency said that standard carcinogenicity tests with the antihistamines in mice and rats do not demonstrate carcinogenicity and the FDA believes that further study is needed before any action is taken. The FDA advised consumers that short term use of the antihistamines is not at issue.
The agency is taking the study seriously, however. Researchers at the FDA plan to duplicate the study and reevaluate the human risk assessment methods. According to Joseph DeGeorge, supervisory pharmacologist in the Division of Oncology and Pulmonary Drug Products at the FDA, researchers will not only duplicate the study, but will extend their research to include modifications to Brandes' work. For example, DeGeorge said that human tumors may different than the tumor types that Brandes used. "We are trying to extend to other tumor types and other assays." The FDA is interacting very closely with Brandes in duplicating his work, DeGeorge said.
The FDA will also examine another innovative method used in Brandes' study pertaining to how tumors respond to increasing doses of antihistamines. Brandes found that the dose-response rate forms a bell curve, with little response at low doses and high doses, and heavy response at mid-sized doses. In the past, researchers have generally assumed that response increases linearly as dose increases.
Brandes' finding implies that traditional research involving only the administration of high doses could have missed high levels of response at mid-sized doses.
Meeting of the Cancer Minds
Cancer chaos.
There are as many theories on how cancer is caused as there are scientists studying it.
Image credit: Carlos Sonnenschein/Ana Soto
A recent meeting brought together scientists conducting cancer research using information gained from studies using species "ranging from bacteria to yeast to fruit flies to mice to humans," as described by Richard Paules, coordinator of the conference on Molecular Mechanisms of Environmental Carcinogenesis. The meeting, held at the NIEHS September 19-20, was a chance for researchers from diverse areas to present the most recent advancements in environmental cancer reseach.
Perhaps the most exciting and certainly the most publicized information presented at the conference was the isolation of
BRCA1
, the gene for inherited susceptibility to breast cancer by a team of researchers from several institutions including the NIEHS and the University of Utah School of Medicine. Several other presentations highlighted recent advance in cancer knowledge in such areas as the varying consequences of genetic damage in animals with different genetic backgrounds; the correlation between the appearance of Li-Fraumeni syndrome in young children caused by genetic mutations in the p53 gene and the appearance of cancers from the same type of mutations in their parents and grandparents later in life; identification of a mutation in an area of chromosome 14q which may be developed as a prognostic tool for endometrial cancer; and an update on research of the effect of exogenous estrogens on rates of endometrial and breast cancers.
Researcher Amy Moser of the McArdle Laboratory for Cancer Research at the University of Wisconsin School of Medicine presented studies supporting the theory that particular genetic mutations, in combination with particular environmental toxicants, may result in different consequences; for example, mutations may produce a lot of tumors or no tumors depending on the genetic makeup of the individual in which they occur. Moser's studies involved mice with a Min (multiple intestinal neoplasia) mutation in a gene that appears to be involved in human colon cancers. This mutation predisposes mice to intestinal tumors, and mammary tumors in the presence of ethylnitrosourea, an alkylating agent that damages DNA. Moser and colleagues also identified a gene, named
MOM
-1 (modifier of Min-1) that reduces the number of tumors the mice will get due to the Min-1 mutation.
Scientists from the M.D. Anderson Cancer Center at the University of Texas Medical Center presented epidemiological research on the inheritance of germline p53 mutations which suggests that environmental factors may affect the development of tumors. Epidemiologist Louise Strong and colleagues characterized the incidence of Li-Fraumeni Syndrome-type soft tissue sarcomas and osteosarcomas in 20 U.S. and Canadian families not previously identified as cancer carriers. When looking at families of children (aged 6-16) who had Li-Fraumeni syndrome, Strong found that the parents and grandparents of these children also developed Li-Fraumeni-type cancers later in life (in their 50s and 60s). This finding is significant because it may show that environmental factors are acting on the increased genetic instability due to the p53 mutations passed through the germline causing these cancers to occur at younger and younger ages in consecutive generations. According to Strong, this approach to studying families may allow researchers to determine cancer risk by sex, generation, mutation type, and cancer site in carriers of p53 germline mutations.
Research presented by Jeff Boyd of the University of Pennsylvania Medical Center may be useful in determining which women with endometrial cancer will have a poor prognosis from the disease. Boyd has identified a mutation in chromosome 14q that correlates with terminal type II endometrial cancers. Scientists may potentially use this genetic marker as a prognostic tool. This mutation may also be involved in the development of other estrogen-related cancers as well.
Epidemiologist Barbara S. Hulka of the University of North Carolina School of Public Health provided an update on the relative risk to women of cancer from exposure to exogenous estrogens through use of oral contraceptives and estrogen replacement therapy (ERT). Hulka stated that use of ERT over periods of 10-15 years may increase the risk of endometrial cancer by as much as 10-fold; however, this risk may be reduced or eliminated by adding progestin to the therapy. Similarly, use of combined estrogen/progestin oral contraceptives for 3-5 years also reduces the risk of endometrial cancer to half that of nonusers. However, women who begin use of combination product oral contraceptives as teenagers may slightly increase their risk of breast cancer.
Paules said of the meeting, "I think it is really important for cancer researchers to see the diversity of research. We get very focused on our own little areas . . . It's really important to step back and look at the broader picture of cancer research to see how to better design our experiments and where we fit in." Over 250 scientists attended the conference, which was co-sponsored by Burroughs Wellcome, the Chemical Industry Institute of Toxicology, the Genotoxicity and Environmental Mutagen Society, Glaxo, the North Carolina Biotechnology Center, and Procter & Gamble.
Taking the Lead on Lead
"In some cases soil cleanup benefits human health, but in other cases, a community may panic, spend millions of dollars on cleanup, then find it hasn't helped," said Bobby Wixson, chairman of the international Society for Environmental Geochemistry and Health task force on lead in soil, in announcing a new approach to lead cleanup.
SEGH's report, which calls for a flexible, case-by-case approach to risk assessment for lead in soil, is the result of six years of study of the issue by the task force, which included scientists, physicians, environmental regulators, and industry representatives. "This is the most comprehensive scientific study to date on this issue," said Brian E. Davies, an internationally recognized soil scientist and co-chairman of the SEGH task force.
The task force proposes an approach which moves away from the "dirt-eating child" test for what levels of lead may remain in soil, to a formula that takes into account factors such as the future use of the property (for example, as an industrial site versus a playground); actual levels of lead in the blood of affected people in the area; bioavailability of lead--that is, its ability to be absorbed by the body--which varies with lead's composition and particle size; and economic factors. Wixson said, "This system will help communities decide the best use of their money to protect the most people."
According to the SEGH report, as of 1993, lead had been found at 922 of the 1,300 Superfund sites slated for priority cleanup by the EPA. However, factors such as pollution from leaded gasoline, flaking lead paint, and other sources of lead contamination complicate cleanup issues.
The Threat of Lead
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Children, because of their body size and play habits, are most vulnerable to lead in soil.
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Lead occurs naturally in soil up to 120 ppm.
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Research suggests that more than 25% of urban gardens contain more than 500 ppm lead.
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One study in Maryland found garden soil lead levels as high as 5,000 ppm.
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Even nonurban areas are affected by residues from leaded gasoline, lead-based paints, and other pollutants.
Soil solutions.
New approaches to lead cleanup take into account the particular sensitivities of children to lead's effects. Statistics: SEGH Task Force on Lead in Soil.
The EPA estimates that 12 million U.S. children under age 6 may be exposed to soil with high levels of toxic lead. Because health effects of lead exposure may include reduced intelligence and growth in children, miscarriage and premature birth in pregnant women, and lowered birth weight and decreased mental ability in infants born to exposed mothers, the EPA considers lead poisoning to be the most serious environmental health threat to young children.
Panelist Rufus Chaney of the USDA's Agricultural Research Service estimates more than 23% of urban gardens may contain more than 500 ppm of lead. Studies at Central Michigan University indicate the problem is not just urban, citing findings of median lead levels in soil near the foundation of older homes of 960 ppm. Currently, under EPA standards, soil with more than 500 to 1,000 parts per million of lead is considered hazardous and cleanup is recommended. The SEGH panel opposes setting a single ceiling for lead in soil above which cleanup would be recommended, preferring a case-by-case approach.
According to the SEGH report, the task force's proposed formula allows for future adjustment and is also flexible enough to be used internationally, though environmental standards for lead vary from country to country. "Still," said Davies, "our result is a starting point, not an end point. We need to test these guidelines in real-world situations. New information will change some of the current concepts. That's the way it should be."
To MTBE or Not to MTBE
Adding to the problem?
New information fuels the debate over oxygenated gasoline.
Photo credit: Joseph Tart
Current efforts to protect people from the dangers of carbon monoxide may be doing more harm than good. In response to findings that levels of carbon monoxide were unusually high throughout U.S. cities, the EPA mandated in 1992 that every state add the oxygenates ethanol and methyl tertiary butyl ether (MTBE) to gasoline to reduce carbon monoxide emissions in problem areas. The additives are used during the winter months, when carbon monoxide emissions are highest.
A year after the onset of the oxygenated fuels program, the results in some states haven't been what the EPA expected. North Carolina is one state where the program has not significantly reduced carbon monoxide emissions.
In addition, studies have shown that MTBE may be a carcinogen. The toxicity of MTBE has become a major concern because inhalation exposure to the compound is widespread. There is also potential for contamination of drinking water from gasoline spills and leakage from underground storage tanks.
Two studies have found that MTBE causes tumors in mice and rats. An inhalation study, conducted by H.D. Burleigh-Flayer and colleagues at the Bushy Run Research Center, Union Carbide Chemicals and Plastics Company, Inc., in 1992 exposed groups of 50 CD-1 male and female mice to MTBE at concentrations of 400, 3,000, and 8,000 parts per million (ppm) for 6 hours a day, 5 days a week, for 18 months. The MTBE caused an increase of liver tumors at the highest dose. There was a statistically significant increase in adenomas in female mice, and a statistically significant increase in carcinomas in male mice. However, the study had to be terminated early (at 18 months rather than 24 months as planned) due to high-dose toxic effects. Therefore, whether MTBE would have affected mice in the lower-dose groups if the study had continued is not known.
In an inhalation study conducted by J.S. Chun and co-workers, also of Bushy Run, in 1992, groups of 50 F344 rats were exposed to MTBE at the same concentrations as in previous study. The low-dose group was exposed for 24 months, the mid-dose group for 97 weeks, and the high-dose group for only 82 weeks, due to toxicity leading to early mortality. In mid- and high-dose groups of male rats, a statistically significant increase in interstitial cell testicular tumors occurred that was clearly dose related. The number of tumors in control groups were high, but an increased number of tumors in the treated groups was apparent. Male rats in mid- and high-dose groups also developed significant increases in kidney tumors.
Preliminary results from an ongoing study being conducted by Cesare Maltoni and colleagues at the Collegium Ramazzini in Italy also contribute to the weight of information on the toxicity of MTBE. This study subjected Sprague Dawley rats to MTBE by olive oil gavage for the lifetime of the rats. Increases in several types of tumors occurred at 250 milograms per kilogram (mg/kg) and 1000 mg/kg MTBE, including malignant sarcomas, testicular Leydig cell tumors, hemolymphoreticular tumors, and combined lymphomas and leukemias. Not all dose groups have been reported. Although these results are preliminary, they are notable because tumors are being seen at much lower concentrations of MTBE than in the other two studies.
The EPA conducted a risk assessment study last year using the results of the Burleigh-Flayer and Chun studies, and tentatively determined that there was no risk to humans. The EPA concluded that there was not enough evidence to assess the risk of MTBE because there are no pertinent human data and stated that the controversy around the animal studies warranted further evaluation. The EPA cited "major uncertainties" in the database of the rodent research, pertaining to high-dose toxicity, possible species specificity, and high spontaneous background tumor incidence.
The EPA did consider Maltoni's results, but decided they were too preliminary at the time to affect the risk assessment. No final classification of MTBE was made. MTBE was assigned a tentative "C" classification, a possible human carcinogen, based on limited evidence.
Although Maltoni's results have yet to be released, the existing evidence that MTBE may be a human carcinogen has led North Carolina officials to question its use. A report on the public health impact of the oxygenated fuels program was written by the Environmental Epidemiology Section of the North Carolina Department of Environment, Health and Natural Resources. The authors of the report concluded that "the oxygenated fuels program utilizing MTBE does not provide any public health benefit in North Carolina at this time and may indeed be posing an increased health risk to the public."
The scientific advisory board to the DEHNR in the Division of Environmental Management recently evaluated the evidence. The scientific advisory board conducted its own risk assessment and concluded that, according to the National Toxicology Program classification of carcinogenic activity, there is "some evidence" for carcinogenicity of MTBE. The board added that if the details of the Maltoni study are released and reviewed and the preliminary results are confirmed, the data may support "clear evidence of carcinogenicity."
The board also took into account that there are other carcinogens already in gasoline, such as benzene (a class "A," or known carcinogen). An argument in favor of MTBE use is that it reduces the amount of benzene in gasoline. However, as the board acknowledged, MTBE could act synergistically with benzene, producing adverse health effects. Because there is no evidence on the interactions between benzene and MTBE, the board could not determine whether the addition of MTBE alters the chemical composition of gasoline for the better or worse.
The board concluded that the state should consider requesting that the EPA remove MTBE from gasoline because of the uncertainties surrounding it.
Last Update: June 23, 1998