Rural Coalition Meeting
Kenneth Olden, NIEHS director, addressed members of the Rural Coalition on Environmental Health at their annual meeting in March at the historic Penn Center in South Carolina. The rural coalition, a multicultural, national alliance of organizations concerned with rural needs and issues, is committed to grassroots solutions to rural problems. Among the issues the coalition addresses are the health concerns of many rural communities faced with exposures to pesticides, hazardous waste, nuclear materials, and other environmental hazards.
Olden, a federal leader on issues of environmental justice, the concern that lower socioeconomic groups and minorities suffer greater exposure to pollutants and their associated health effects, told the more than 200 participants at the Rural Coalition meeting, "NIEHS is committed to a new paradigm for environmental health research, one that includes high-risk communities and workers as active participants in all aspects of the research venture."
Coalition building.(left to right) Carlos Marentes of Sin Fronteras Organizing Project, Mary Lee Johns of Oyati Zani (Healthy People), Director Kenneth Olden of NIEHS, Executive Director Lorette Picciano-Hansen.of the Rural Coalition, and Pat Bellanger of the American Indian Movement. Photo: NIEHS.
NIEHS to Study Developmental Effects of Pesticides
In 1988, Congress asked the National Academy of Sciences to review the policies and issues surrounding the question of pesticides in food and, specifically, to find out what is known about infantile and juvenile exposures to food-borne pesticides, the adequacy of the current risk assessment procedures, and to identify the most significant toxicologic issues. The NAS convened a panel which released its report in the spring of 1993. The panel found significant differences between the diets of children and adults, quantitative and qualitative differences between children and adults in their susceptibilities to chemical toxicities, as well as the extents of their exposures to pesticides. That is, compared to adults, children are exposed to different amounts of pesticides as well as to a different mix of pesticides. Their exposure to turf chemicals, for example, can be much higher than adults. Additionally, the responses of children to a compound can differ both in kind and magnitude. This is because of the postnatal development that occurs in certain organ systems of humans; alterations in some developmental steps can result in long-term changes in the function of the affected organ. For example, exogenous compounds can delay or hasten the time when testicular Sertoli cells stop dividing, which can result in adult testes that are larger or smaller than normal. Similarly, in the brain, each developmental step builds upon the ones preceding it, so if an alteration in an early step leads to altered neural network formation, decreased learning ability results.
The panel identified three systems as being of special concern, because they undergo substantial development during the early years of life: the central nervous system, the immune system, and the reproductive system.
The panel found that human protection from pesticide risks was based on toxicology data taken from adult animals. The extrapolation of toxic effects data from adult test animals to juvenile humans clearly leaves open the possibility that some adverse effects, particularly effects on developing body systems, might be overlooked. The panel noted that there are huge data gaps in this area and concluded that there have been too few studies in juveniles to justify the continued use of adult data to estimate hazards in juveniles. Even in the relatively small database that exists, the panel found suggestions of significant differences in responses of juveniles and adults.
Robert Chapin Photo: NIEHS
The panel called for changes in regulatory practices and for a systematic evaluation of the relative risks to juveniles and adults. In response, Robert Chapin and his colleagues in the Reproductive Toxicology Group of the Environmental Toxicology Program are designing a study to address this issue. Although initially focused on the reproductive system, the study has been expanded to include evaluations of central nervous system effects and effects on immune system function. These additional studies will be carried out in collaboration with investigators at EPA's Health Effects Research Laboratories. Ginger Moser, Stephanie Padilla, and Robert McPhail will evaluate the central nervous system effects, and Ralph Smialowicz will assess immune system function.
Pregnant female rats will be dosed for the last trimester of pregnancy through the seventh day after birth, and the offspring will be exposed directly. Neurotoxicity, reproductive and immune toxicity will then be assessed at critical stages of offspring development. In addition, some mothers will be milked to determine the amount of test chemical (or its metabolites) in milk. This will provide some information on the amount of test chemical to which the offspring are exposed during their first week of nursing. Some indices of general milk quality will be measured as well.
Animals in the neurotoxicity studies will be evaluated for both general behavior and for learning capability while they are maturing. As adults, they will undergo a series of complex learning/relearning trials to probe for subtle changes in integrated brain function. Reproductive toxicity will be evaluated using a number of indices of sexual development and puberty and, in adult animals, a thorough assessment of reproductive function and structure. Exposed animals will be paired with untreated mates to identify which gender is affected. Hormone and ovulation studies may be conducted if there is evidence that ovulation was impaired in the exposed females. A subset of animals in immunotoxicity studies will be exposed to evaluate their immune responses in vivo, while others will provide tissues for in vitro evaluation of various immune cellular functions.
Study chemicals were chosen to represent a variety of structures and classes of pesticides. In the first study, methoxychlor will be used as a positive control based on data from Earl Gray and colleagues at EPA. They have shown that methoxychlor has significant reproductive effects in animals exposed as juveniles. Tebuconazole is representative of a widely used class of antifungal compounds that exhibit reproductive and developmental toxicities. The organophosphates are represented by chlorpyrifos, a relatively long-acting organophosphate, and parathion, a relatively short-acting organophosphate. Carbaryl will represent the carbamates, another neuroactive class that may have reproductive effects. Atrazine will be evaluated based on its heavy use in the United States, its prevalence in groundwater supplies, and its reported reproductive activity. Finally, trichlorfon, another organophosphate, is included because it has been reported to be associated with adverse reproductive outcomes in humans.
Because the organophosphates and carbaryl alter neurochemical enzymes in known ways, the degree of these effects will be monitored in animals sacrificed both during and after exposure. Acetylcholinesterase inhibition will be evaluated at EPA and also by Mohammed Abou-Donia at Duke University. This will allow a correlation between a known amount of enzyme inhibition and subsequent behavioral and cognitive function.
By comparing the effects and effective doses in these young animals with those from adults, researchers will be able to tell if there are significant differences between these age groups and will have some appreciation for the degree of the problem, if one exists. If the data suggest that the health risks from juvenile exposures to pesticides has been underestimated, these studies will be the first step in a larger evaluation of the problem.
Testing timeline. NIEHS researchers are designing a study to look at the effects of pesticide exposure on the nervous, immune, and reproductive systems of juveniles. Graphic: NIEHS
Frontiersman of Science
Stanley Cohen, who shared the Nobel Prize in 1986 in physiology and medicine for his pioneering discoveries of growth factors, was the keynote speaker at the April "Frontiers of Science Mini-Symposium" sponsored by NIEHS. Cohen's symposium was titled "Growth Factors and Related Signaling Pathways." At the symposium, presentations outlining recent, exciting findings were given by prominent scientists from UNC-Chapel Hill, Duke University, Glaxo Research Institute, and NIEHS.
Growth factors are small proteins that are produced by nearly all tissues and provide potent, local signals that affect behavior of nearby cells or even cells that produce the factor. The various cellular activities regulated by growth factors are extensive and include such events as cell growth and maturation, cell repair, and transport of ions. Specific receptors at the surface of cells determine whether a cell will recognize a particular growth factor.
In his keynote address, Cohen detailed the large body of his research, giving a context for the symposium's other presentations. He reviewed his pioneering Nobel Prize-winning work of 30 years ago on the purification of epidermal growth factor (EGF). His subsequent work has led to the characterization of the response of cells and organisms to EGF stimulation, while his recent work has focused on the specific biochemical changes induced by EGF binding to its receptor in the cell membrane. This binding activates the receptor's enzymatic activity, leading to its interaction with other cellular proteins which lead to metabolic changes in the EGF-stimulated cell.
Since Cohen's pioneering work in growth factor research, hundreds of growth factors have been discovered. The function of many of these factors, however, remains elusive. Many researchers are currently attempting to learn more about the large number of biochemical changes that occur in cells following interaction of growth factors with complementary receptors. Understanding these regulatory circuits in cells might provide insight into the origins of some diseases. Cancer cells, for instance, exhibit changes at nearly every level of some growth factor pathways and many investigations are currently attempting to link specific changes in these pathways with the capacity of cells to change into cancer cells.
Goldstein on Risk Assessment
Bernard D. Goldstein spoke at the Risk Assessment Research Seminar Series on April 22 at NIEHS on comparative risk assessment. Goldstein is the director of the Environmental and Occupational Health Sciences Institute and chair of the Department of Environmental and Community Medicine at University of Medicine and Dentistry of New Jersey.
Using the Valdez, Alaska, oil terminal and attendant exposure of the seaport town citizens to benzene emanating from petroleum handled through the terminal as one example, Goldstein reviewed a number of risk assessment issues. He noted that the risk assessment agenda has never been set by scientific experts but is always strongly affected by economic, political, and social issues.
He also pointed out that there are two often contradictory approaches used in regulatory science: consensus building, such as would be used on a scientific panel, and the confrontational or adversarial approach used in litigation. Both methods are an attempt to ascertain the truth, but the results are often quite different. "What's desired is often a yes-no answer, whereas the choices involve discrete differences between elements in a continuum," Goldstein said.
Goldstein pointed out that psychology is a strong element in perception of risk. During the polio epidemic of the 1950s, more children died of measles than of polio, but because measles was well known and most children recovered from it, measles did not alarm people to the same degree. (As an aside, he mentioned that development of the polio vaccine paved the way for an equally effective measles vaccine.) Another example: radon gas does not excite people as much as other pollutants because there is no "bad guy," no one to blame because radon is a product of nature.
Cooper Receives Lilienfeld Prize
Glinda Cooper Photo: NIEHS
Glinda Cooper, the newest member of the NIEHS Epidemiology Branch, has won the 1994 Abraham Lilienfeld Prize, awarded annually by the Society for Epidemiologic Research for the best paper based on a doctoral dissertation. Cooper presented her paper, "Galactose Consumption, Metabolism, and FSH Concentrations in Women of Late Reproductive Age" at a plenary session of the society's annual meeting June 16 in Miami.
Lactose is a sugar found in milk and milk products and is composed of glucose and galactose. Galactose has been suggested to be toxic to the ovary. Cooper's study examined the galactose consumption of 295 women approaching menopause (ages 38 to 49). Their blood was tested to determine levels of a specific transferase enzyme that breaks down galactose and for levels of FSH, follicle-stimulating hormone, that increase as ovarian function declines before menopause. Women who consumed six or more grams per day of galactose (about one glass of milk or a one-serving container of yogurt) had FSH levels 30% higher than those who consumed less than six grams per day. FSH concentrations were also 65% higher among smokers compared to nonsmokers. This study provides evidence of the sensitivity of the ovary to specific toxic agents, particularly during the years of naturally declining ovarian function that precede menopause.
"Dr. Cooper is the second NIEHS epidemiologist to be awarded this national prize," commented Allen Wilcox, chief of the Epidemiology Branch. "Dr. Andrew Rowland was the winner in 1990 for his work on fertility impairment among women occupationally exposed to nitrous oxide. We're very proud of both of these young researchers."
NIEHS Initiatives
Agricultural Chemicals
Although agricultural chemicals improve crop yields, increase the quality of the American diet, and contribute to improvements in public health, there is growing public concern about their human health effects. Agricultural chemicals are usually mixtures of chemicals, some of which can damage the environment and accumulate in ecosystems. Depending on dose, some agricultural chemicals can cause a range of adverse effects on human health including cancer, acute and chronic injury to the nervous system, lung damage, reproductive dysfunction, and possibly dysfunction of the endocrine and immune systems.
There are many gaps in information about the mechanisms of toxic action, human exposures, and the nature and extent of human health effects of agricultural chemicals. Very few older pesticides, in particular, have been tested for human health effects. NIEHS has long supported activities on the impact of agricultural chemicals on human health. From this experience and several recent conferences, NIEHS has identified some new initiatives and additions to current efforts that could significantly improve our knowledge about adverse health effects of agricultural chemicals, especially in susceptible populations.
To establish valid and accurate risk assessments, sound information on how agricultural chemicals are involved in toxicity and their mechanisms of action must be generated. This information must include data on exposure assessment, tumor promotion, chronic and acute neurotoxicity, immunotoxicity, and reproductive and developmental toxicity. New research and development efforts of NIEHS will concentrate on:
- Epidemiology studies of chronic or low-level exposures to agricultural chemicals, especially in the susceptible populations of women, children, the elderly, and migrant workers.
- Epidemiology studies of delayed neuro- and immunotoxicity of agricultural chemicals in susceptible populations.
- Identification of more biochemically and pathophysiologically specific biomarkers of exposure and effects of agricultural chemicals (e.g., use of new cellular biochemistry to find biomarkers of effects on cell function).
- Studies of both cancer and noncancer endpoints of agricultural chemical exposures including tumor promotion, chronic and acute neurotoxicity, immunotoxicity, and reproductive and developmental toxicity.
- Studies investigating the mechanisms of action of these chemicals as a way to better understand the effects of agricultural chemicals in previously exposed individuals and as a means to develop prevention and/or intervention strategies.
- Development of methods to study ecological effects of agricultural chemicals as an indicator of potential human health hazards.
A number of animal and clinical trials have demonstrated the relative sensitivity of pregnant women and their fetuses to the neurotoxic and reproductive and developmental toxicity to agricultural pesticides. Both quantitative and occasionally qualitative differences in toxicity of agricultural pesticides between children and adults have been found. Certain epidemiology studies suggest that long-delayed adverse health effects of agricultural chemicals can occur (e.g., parkinsonian-like symptoms years after exposure, breast cancer years after exposure). Migrant workers and their families are likely to be studied for agricultural chemical effects. New tests for noncancer endpoints and biomarkers for pesticide exposures are now available which could be used to identify populations at greatest risk for adverse effects.
The health effects of agricultural chemicals are of concern to many. Putting the risks in better perspective and devising useful and effective identification, intervention, and prevention techniques will go far toward understanding and managing the health risks associated with exposures. New NIEHS initiatives are needed to address the concerns of groups recently identified as more affected or susceptible, especially children, pregnant women and their fetuses, and migrant workers, a large percentage of whom are minorities.
Lead and Other Metals
Metals are ubiquitous and persistent pollutants, present in food, water, ambient air, and most waste dumps. Metals can cause or contribute to many serious health problems such as birth defects, adverse mental and behavioral effects, and nerve, kidney, and cardiovascular disease. Although some of the health effects of lead exposure are well publicized (e.g., long-term neurocognitive deficits seen even with low exposures), concerns about the potential health effects of other metals such as cadmium, arsenic, beryllium, and mercury are still evolving and merit new efforts and increased attention. These concerns may be especially true for the elderly who have large body stores of possibly mobilizable metals like lead and cadmium.
New research is needed on human health effects of selected metals. Efforts specifically targeted to development of new methods and models are required. The following represent some current pressing needs identified at recent meetings sponsored by NIEHS.
- Establish new epidemiology studies to link metals with specific diseases--e.g., osteoporosis, Parkinson's and Alzheimer's diseases in the middle aged and elderly.
- Develop better animal models of diseases caused by metals.
- Develop transgenic animals that respond to metal toxicity the same way humans do.
- Study in animals and humans the role of the skeleton as dosimeter, reservoir, and target for bone-seeking metals (e.g., lead and cadmium). Apply this research to better intervention and prevention of metal release from tissues in pregnancy and old age.
- Better characterize differences between effects of acute and chronic exposures to metals for children and adults.
- Study mechanisms of metal toxicity (e.g., receptors, cell messengers, growth factors). Use such findings to better detect, treat, and prevent metal toxicity.
- Develop more effective and specific chelators to prevent and treat metal toxicity, especially cadmium and mercury.
- Develop new and better tests for low-level effects of toxic metals like mercury (e.g., neurocognitive and behavioral tests).
- Define relationships between nutritionally essential metals (e.g., calcium, iron, zinc, selenium) and toxicity of metals like lead, mercury, cadmium, etc.
Recent research has identified toxic effects of low concentrations of metals which had not previously been recognized. As a consequence, large, susceptible populations (e.g., pregnant women, fetuses, children, those consuming large amounts of fish) have been identified that are at risk from low-level metal exposures not previously known to be harmful. Public health initiatives to reduce exposures to metals are largely based on NIEHS research. Several noncancer effects of metals such as effects on the brain/nervous system and excretory organs have been explored in detail. Some specific targets have been identified (e.g., parts of the brain for lead/mercury, and renal tubules for cadmium). New interventions are being studied or developed for some metals. The new NIEHS efforts could have major impacts on establishing the now unknown contributions of metals to several diseases. Improved intervention and treatment of effects could then follow. Better models for the effects of metals coupled with understanding of mechanisms, will be the key to safer and more effective intervention and prevention.
Last Update: July 15, 1998