COOPERATIVE EXTENSION UNIVERSITY OF CALIFORNIAENVIRONMENTAL TOXICOLOGY NEWSLETTER

COOPERATIVE EXTENSION UNIVERSITY OF CALIFORNIA
ENVIRONMENTAL TOXICOLOGY NEWSLETTER

This issue of the Environmental Toxicology Newsletter is the last that will be sent without subscriptions. Subscription information is attached and it is my hope that there will be enough support to continue outside circulation of the newsletter. It also marks the first appearance of a guest author, Ed Littrel, who works for the Department of Fish and Game in the Pesticide Investigation Unit. Ed's article on diazinon toxicity to waterfowl should be of particular interest to persons involved with turf management.

Most of this issue is devoted to some very recent reports on dioxin (TCDD), occupational causes of cancer, and epidemiologic data on the substances most often involved in cases of acute poisoning in children.

The Department of Fish and Game (DFG) pesticide laboratory was informed in January 1984 that up to 40 widgeon ducks had died at a golf course in Southern California. The DFG's pesticide wildlife biologist examined two of these birds. He suspected diazinon was the causative agent because there has been a recorded history of widgeon being killed under similar circumstances. Subsequent chemical analyses of liver tissue, crop contents and turf from the golf course confirmed the presence of diazinon at toxic levels.

Diazinon is an organophosphate insecticide used for a variety of pests. Here, it was used to control turf-dwelling grubs or larvae. The following are examples of recorded diazinon poisoning incidents under similar circumstances.

In 1972, 500 widgeon died at Seal Beach, California. Toxic levels of diazinon were detected in gizzard contents and turf. Canada geese were killed by diazinon in Missouri in 1975. These birds exhibited depressed acetyl cholinesterase activity. A grass sample from the mouth of a bird was found to have high diazinon levels. This loss was especially notable as the diazinon had been applied in August, three months prior to the loss in November.

Another incident occurred in 1976 at a Los Alamitos, California golf course when approximately 100 widgeon and coots were killed due to an application of diazinon. Significant diazinon residues were detected in the birds' digestive tracts. Diazinon had been applied one month prior to the mortality.

A hazard to grazing waterfowl (widgeon, coots, geese) may develop when diazinon is applied to golf courses for grub control. This hazard may continue for one to three months after application. The "greens" areas of golf courses near water have the greatest potential for trouble, especially the fringe of the green where grass is one to two inches high. Diazinon is typically used on greens for insect control, and the fringe area is most attractive to waterfowl as it is the best height for their feeding habits.

Greenskeepers, PCO's, and advisers should be alert to the hazard of using diazinon in the fall and winter or any time when waterfowl are present. The California Department of Fish and Game would be interested in your observations on this problem, or any other pesticide problems related to fish and wildlife.

Adequate dose-response data for chronic effects of TCDD are not available from epidemiologic studies of humans. Therefore, extrapolations from animal toxicity experiments (including carcinogenicity and reproduction effects) to possible human health effects have been used to estimate a reasonable level of risk from exposure to this agent. Extrapolations have been derived from a review of published studies; a complex set of assumptions related to human exposure to contaminated soil; and estimates of (1) a dose-response curve, (2) appropriate margins of safety, and/or (3) applicable mechanisms of action.

TCDD is a known carcinogen in animals, and there is considerable discussion about the best way to calculate excess cancer risk in humans exposed to TCDD. General issues of concern include use of appropriate mathematical models for predicting responses at the low end of the dose-response curve, how to use dose-response data from different tissue sites, (e.g., liver, lung) and what conversion factors to use in extrapolating from animals to humans to account for species variations. Using data from previous toxicologic studies with female rats, dose-response estimates were derived. The lower boundary of the confidence interval for a dose estimated to increase the risk of developing cancer by one per million was then calculated. For liver cancer (the most sensitive tissue site), a virtually safe dose (VSD) was estimated as 28 femtograms (fg)* per kg body weight (b.w.) per day. For the risk of inducing tumors in less sensitive tissues, a VSD of 1,428 fg/kg b.w./day was estimated. These doses were then extrapolated directly to humans. The model used was linear; therefore, the levels for an increased risk of one excess cancer per 100,000 are 276 fg to 14.3 picograms (pg)*/kg b.w./day.

* miiligram, mg = 10xE-3 g; microgram, ug = 10xE-6 g; nanogram, ng = 10xE-9 g; picogram, pg = 10-12g; femtogram, fg = 10xE-15 g.

One ppb of TCDD in residential soil was chosen as a level of concern, and at substantially higher levels (e.g., greater than 100 ppb TCDD in soil), calculated risks may increase.

The level of concern for 2,3,7,8-TCDD in soil should not be viewed as a universal standard but rather as an operational starting point to analyze each situation. Characteristics unique to each situation - including locations of the contaminated soil, composition of the population exposed, and the likely frequency and duration of future exposures - factor significantly in assessing each case.

In assessing the implications of this level of concern for any particular site, one should use additional information and recognize a complex set of underlying assumptions, such as the amount of TCDD people might receive, how often they are exposed, and whether humans have the same response to TCDD as animals. To err on the side of public safety, these assumptions should be conservative and should address factors related to: uniformity of TCDD concentration in soil; uniformity of human access (particularly children's access) to and activity on the soil; intensity, frequency, and duration of exposure; and the bioavailability of TCDD in different soils and through different types of exposure. Furthermore, when soil is measured for TCDD concentration, the adequacy of the sampling plan, the degree of laboratory extraction of TCDD from soil, and the accuracy of its subsequent measurement must be considered.

Results of a Pilot Study of Health Effects due to 2,3,7,8-Tetrachlorodibenzodioxin Contamination - Missouri

Comparisons of these two groups produced no consistent indications of increased disease prevalence directly related to the putative exposures; no cases of chloracne, overt porphyria cutanea tarda (PCT, an acquired form of porphyria characterized by chronic skin lesions and other symptoms.) or precursor conditions of PCT, or soft-tissue sarcomas were seen. An apparent trend of urinary-tract abnormalities was indicated by an increased prevalence of self-reported kidney/urinary problems, a higher proportion of leukocyturia (white blood cells in the urine) and a greater prevalence of microscopic hematuria (red blood cells in urine) in the group at high risk of exposure. None of the findings from the medical histories or the immune- function assays demonstrated statistically significant differences. There was, however, an indication of an increased prevalence of T4/T8-cell (white blood cells involved in cellular immunity) ratios less then 1.0 in the high-risk group. No significant differences in standard and specialized liver- function test results were detected.

This pilot study of a group of individuals presumed to be at high risk of exposure was intended to provide a perspective on the types and degrees of abnormalities likely to be seen in such TCDD exposures. The results appear negative, but no overall definitive conclusion should be based solely on this initial study. The insights provided need to be examined in more refined epidemiologic studies using different designs and strategies (especially in larger, more homogeneous population groups in which exposure status can be better characterized). These studies should be focused primarily, but not exclusively, on discerning any effects on the immune and neurologic systems and the urinary tract and liver.

Editorial Note: Animal toxicity studies are commonly used to predict health effects in humans (although the existence of species-specific and even organ-specific effects of TCDD make extrapolations tenuous). The organ systems most prominently affected in animals are the liver (acute toxicity and hepatocarcinogenesis), the immune system (thymic atrophy and decreased cell-mediated immunity), and the skin (chloracne-like changes); effects on reproduction have also been noted.

In some workplaces, exposed persons had chloracne but no systemic illnesses; other reports have noted that workers fatigued easily and experienced weight loss, myalgias (muscle pain), insomnia, irritability, and decreased libido. The liver has been shown to become tender and enlarged, and sensory changes, particularly in the lower extremities, have been reported.

In Missouri, after playing in dirt in a riding arena contaminated with up to 33 parts per million TCDD, a child had hemorrhagic cystitis (inflammation of the bladder).

Porphyria Cutanea Tarda and Sarcoma in a Worker Exposed to 2,3,7,8-Tetrachlorodibenzodioxin - Missouri

A former worker had developed porphyria cutanea tarda and sarcoma. The worker, a 59-year-old male, had been in good health until June 1982, when he developed blistering and increased hair growth over the dorsa (back) of his hands. Subsequent medical investigation confirmed a diagnosis of porphyria cutanea tarda.

The man was found to have multiple lytic lesions of his proximal right femur and pelvis, with involvement of adjacent soft tissue. Biopsy of the right ilium revealed a sarcoma. Two consultant pathologists concluded that the tumor was an angiosarcoma; it was not possible, however, to determine whether the tumor arose from bone or soft tissue.

The patient had worked as a truck driver for over 21 years, and in the early 1970s, worked for several years at one of the TCDD-contaminated trucking terminals. Soil samples taken at this terminal in 1983 had shown that TCDD was present in subsurface soil at concentrations as high as 17 parts per billion (ppb). He had worked unhooking trailers from trucks in the sprayed area of the terminal and thus had potentially higher exposure to TCDD than in his usual work as a driver. He reported that his feet, legs, hands, and arms frequently became covered with oil from the terminal. He continued to work at the terminal through early 1980. Also, he occasionally made deliveries to a chemical plant and to other trucking terminals now known to be contaminated with TCDD. He had no history of other exposure to TCDD either at work or at home.

Editorial Note: Although this worker was probably exposed to TCDD through cutaneous absorption of contaminated oil and also by inhalation of aerosolized dust containing TCDD, the possible relationship between this exposure and the development of subsequent disease is far from clear. Chronic alcohol ingestion has been reported to result in porphyria cutanea tarda. Also, porphyria cutanea tarda has been reported in two groups of workers exposed occupationally to TCDD (and possibly also to hexachlorobenzene). In both instances, all cases of porphyria appeared during the time of actual chemical exposure.

Soft-tissue sarcoma is a rare tumor, with an incidence in the general U.S. population of 3.9 per 100,000. Two recent case- control studies in Sweden have shown an approximate sixfold increase in the risk of death from soft-tissue sarcoma among workers with histories of occupational exposures to TCDD- contaminated phenoxy acid herbicides or chlorophenols. Other epidemiologic studies have been inconclusive because of their small study populations and consequent low statistical power. Additionally, a recent analysis of data from three cohort mortality studies of workers exposed at chemical manufacturing plants to TCDD-contaminated trichlorophenol or to the herbicide 2,4,5-trichlorophenoxy acetic acid suggests the existence of an association between TCDD exposure and soft-tissue sarcoma.

NIOSH is continuing to interview and examine workers from TCDD- contaminated trucking sites. In addition, NIOSH is conducting a mortality study and a cross-sectional medical study of workers exposed to TCDD at several chemical plants.

Cancer kills approximately 430,000 people in the United States annually; the American Cancer Society estimates that some form of cancer will develop in one-fourth of all Americans. It is the second leading cause of death and the second leading cause of lost years of potential life in this country. A high proportion of all cancers are thought to be caused by "extragenetic" factors, including behaviors (e.g., cigarette smoking, alcohol and drug use, and sexual activities) and toxic environmental exposures in the workplace and the community. Evidence for these relationships has been developed principally through epidemiologic and toxicologic studies. The main epidemiologic observations have included: differences in the incidence of cancer between groups with different exposures, changes in the incidence of cancer following migrations, changes in the incidence of cancer over time, etc. Toxicologic studies have led to the identification of specific agents that cause cancer in experimental animals.

A possible occupational origin for malignant disease was first recognized when an unusually high frequency of scrotal cancer was observed among London chimney sweeps in 1775. Since then, several types of cancer have been associated with industrial agents or processes. Numerous other occupational agents--such as beryllium, cadmium, ethylene oxide, phenoxy- acetic acids, and chlorophenols--or processes--such as newsprint pressroom work--are suspected of being carcinogenic and are under investigation by NIOSH.

Condition	Industry/occupation	Agent
Hemangiosarcoma of the liver monomer	Vinyl chloride polymerization Industry vintners	Vinyl chloride Arsenical pesticides
Malignant neoplasm of nasal cavities	Woodworkers, cabinet/furniture makers Boot and shoe producers Radium chemists, processors, dial painters Nickel smelting and refining	Hardwood dusts Unknown Radium Nickel
Malignant neoplasm of larnyx	Asbestos industries and utilizers	Asbestos
Mesothelioma (peritoneum) (pleura)	Asbestos industries and utilizers	Asbestos
Malignant neoplasm of bone	Radium chemists, processors, dial painters	Radium
Malignant neoplasm of scrotum	Automatic lathe operators, metalworkers Coke oven workers, refiners, tar distillers	Mineral/cutting oils petroleum soots, tars, tar distillates
Malignant neoplasm of bladder	Rubber and dye workers	Benzidine, alpha and beta, naphthyl-amine, auramine, magenta, 4-aminobi- phenyl, 4-nitro- phenyl
Malignant neoplasm of kidney; other, unspecified urinary organs	Coke oven workers	Coke oven emissions
Lymphoid leukemia, acute	Rubber industry Radiologists	Unknown Ionizing radiation
Myeloid Leukemia, acute	Occupations with exposure to benzene Radiologists	Benzene Ionizing radiation
Erythroleukemia	Occupations with exposure to benzene	Benzene

Although general agreement exists concerning the overall incidence of cancer, considerable controversy surrounds the proportion of cancer cases attributable to occupational exposures. Several characteristics of cancer contribute to the difficulty in making such estimates:

In addition, problems with the documentation of cancer and the nature and extent of etiologic exposures obscure important epidemiologic associations:

Despite these difficulties, various attempts have been made to estimate the proportion of cancers related to occupation. These estimates span a broad range, from less than 4% to more than 20%. While these estimates are obviously imprecise, little doubt remains that occupational factors are significantly related to an increased risk of cancer. Moreover, in specific groups of workers exposed to specific carcinogens, the proportion who ultimately develop occupational cancer may be large. Of one group of workers distilling beta-naphthylamine who had more than 5 years of exposure, all reportedly developed tumors of the bladder; up to 11% of workers exposed to asbestos may ultimately develop mesothelial tumors.

The U.S. Food and Drug Administration (FDA) estimates that the nation's 430 poison control centers are contacted 1.5 million times each year about exposures to potentially toxic substances. In 1981, FDA's Poisoning Surveillance and Epidemiology Branch received over 121,000 reports of product- or substance-specific exposures to suspected poisons. Children under 5 years of age accounted for 60.3% of these exposures, and 13.0% of these were associated with clinical evidence of toxicity. Pharmaceuticals, including both prescription and over-the-counter products, accounted for 40.0% of the exposures (Figure 1). The most common pharmaceutical involved was flavored chewable vitamins (14.1%). After pharmaceuticals, the most frequently reported exposures for children under 5 years of age were to "cleaners, polishes" and plants. The "other, unknown" category of exposures, which includes ingestion of multiple products and illicit substances, accounted for 10.4% of the exposures.

Figure 1. Distribution of exposures to chemical products for children under 5 years of age - United States, 1981

During the second week of March I attended the Society of Toxicology Meeting in Atlanta, Georgia. I attended a Continuing Education course entitled "Current Concepts and Mechanisms of Carcinogenesis", and a number of excellent symposia on topics like TCDD, species differences in toxicological response, and receptor mechanisms in toxicology. In future newsletters I will address some of these topics. To end this newsletter I would like to comment on one paper that was presented in the Species symposium. The title was "Species Difference in Hepatic Peroxisome Proliferation Due to Trichloroethylene: Role of Trichloroacetic Acid Formation" and it was presented by Dr. C.R. Elcombe of the Imperial Chemical Industries Central Toxicology Laboratory. The experiments reported below were done in isolated liver cells in vitro.

Peroxisomes are intracellular organelles that usually occur in low numbers in normal cells. In mice, trichloroethylene (TCE) has been shown to be a liver carcinogen, and TCE causes an increase in peroxisome numbers in mouse liver cells. Thisincrease in peroxisomes and lipid peroxidation is a proposed mechanism of carcinogenic action of TCE in mice. Mice metabolize most of the TCE to trichloroacetic acid (TCA), and TCA alone causes peroxisome proliferation in mice. TCE does not cause liver tumors in rats, and rats metabolize only a small percentage of the TCE dose to TCA. Little proliferation of peroxisomes is seen in rats after TCE. If rat liver cells are exposed to TCA (the metabolite),the cells respond with peroxisome proliferation. This indicates that the metabolite (TCA) is responsible for the proliferation.

Dr. Elcombe extended his experiments to liver tissue taken from brain-dead human donors. The results are fascinating. Human liver cells are similar to rat liver cells in that they metabolize only a small percentage of a TCE dose to TCA, and do not repond with peroxisome proliferation in response to TCE. Human liver cells differ from rat and mouse liver cells in that human liver cells did not respond with peroxisome proliferation when exposed to TCA. Thus, human liver cells would not respond to TCE or TCA according to the proposed mechanism of carcinogenic action of TCE, i.e. peroxisome proliferation. If the mechanism of hepatocarcinogenicity of TCE is indeed via peroxisome proliferation, then humans would be very resistant to the hepatocarcinogenic effects of TCE. The results of this research could have far-reaching implications in risk-assessment. Stay tuned for future developments.