Public health implications of environmental exposures.

The Agency for Toxic Substances and Disease Registry (ATSDR) is a public health agency with responsibility for assessing the public health implications associated with uncontrolled releases of hazardous substances into the environment. The biological effects of low-level exposures are a primary concern in these assessments. One of the tools used by the agency for this purpose is the risk assessment paradigm originally outlined and described by the National Academy of Science in 1983. Because of its design and inherent concepts, risk assessment has been variously employed by a number of environmental and public health agencies and programs as a means to organize information, as a decision support tool, and as a working hypothesis for biologically based inference and extrapolation. Risk assessment has also been the subject of significant critical review. The ATSDR recognizes the utility of both the qualitative and quantitative conclusions provided by traditional risk assessment, but the agency uses such estimates only in the broader context of professional judgment, internal and external peer review, and extensive public review and comment. This multifaceted approach is consistent with the Council on Environmental Quality's description and use of risk analysis as an organizing construct based on sound biomedical and other scientific judgment in concert with risk assessment to define plausible exposure ranges of concern rather than a single numerical estimate that may convey an artificial sense of precision. In this approach biomedical opinion, host factors, mechanistic interpretation, molecular epidemiology, and actual exposure conditions are all critically important in evaluating the significance of environmental exposure to hazardous substances. As such, the ATSDR risk analysis approach is a multidimensional endeavor encompassing not only the components of risk assessment but also the principles of biomedical judgment, risk management, and risk communication. Within this framework of risk analysis, the ATSDR may rely on one or more of a number of interrelated principles and approaches to screen, organize information, set priorities, make decisions, and define future research needs and directions.

The Agency for Toxic Substances and Disease Registry's role in development and application of biomarkers in public health practice.

An overview of the Agency for Toxic Substances and Disease Registry's (ATSDR) biomarker program is presented in the context of the paradigm for biomarkers developed by the National Research Council (NRC, 1987, 1991). The status and projected utility of four biomarker studies conducted by NRC and sponsored by ATSDR, the Environmental Protection Agency (EPA), and the National Institute of Environmental Health Sciences (NIEHS) are discussed. These studies include a review of relevant research on biomarkers for specific toxicologic end points, including reproductive toxicology, pulmonary toxicology, neurotoxicology, and immunotoxicology. Also, the scope of related research on exposure characterization being conducted by the ATSDR-sponsored research program at Rutgers University is reviewed. The potential impact of biomarkers on public health assessments and on the range of ATSDR programs is described. Specifically, the role of biomarkers in dose reconstruction, in ATSDR's health studies program, and in the emerging field of molecular epidemiology is reviewed. In addition, future directions and research needs are addressed.

Abnormal feathering of chicks caused by scirpenol mycotoxins differing in degree of acetylation.

Graded levels of the Fusarium mycotoxins, scirpentriol (STO), 15-monoacetoxyscirpenol (15-MAS), 4,15-diacetoxyscirpenol (4,15-DAS), and 3,4,15-triacetoxyscirpenol (TAS), were fed to chicks until 3 wk of age. The primary wing feathers, which were scored visually on a scale of 1 to 5 using a newly created scoring scheme, were altered in a dose-related fashion by 15-MAS [minimum effective dose (MED) = .5 microgram/g diet], 4,15-DAS (MED = 2 micrograms/g), and STO (MED = 4 micrograms/g) but not by TAS (MED greater than 8 micrograms/g). The minimum growth inhibitory doses were 2 micrograms/g for STO, 15-MAS, and 4,15-DAS and 8 micrograms/g for TAS. The main alteration of the feathers was a frayed and missing web on the medial side of the distal half of the feather. The shafts of the feathers tended to have an accentuated medial curve. These results imply that the feather alterations associated with corn and feed infested with Fusarium spp. might be caused by trichothecene mycotoxins such as the scirpenols.

High dietary fat increases toxicity of diacetoxyscirpenol in chickens.

The influence of high dietary fat on the toxicity of diacetoxyscirpenol (DAS) was investigated in a 2 x 5 factorial arrangement of treatments (6 and 12% fat, and 0, 1, 2, 4, and 8 micrograms DAS/g diet). The 3-wk body weight was decreased (P less than .0001) by DAS, but fat had no significant (P less than .05) effect. There was a highly significant (P less than .0059) interaction manifested at the higher levels of DAS by a greater decrease in body weight in the high-fat diet than in the low-fat diet. Neither feed conversion nor percentage of fat in fecal material were affected significantly (P less than .05) by DAS. These data were consistent with the high-fat diet promoting lipid micellar absorption of DAS and with DAS, once absorbed, inhibiting protein synthesis at the ribosomal level, a well established mechanism of action for trichothecene toxins such as DAS.

Scirpentriol toxicity in young broiler chickens.

Scirpentriol (STO) (3 alpha,4 beta,15-trihydroxy-12,13-epoxytrichothec-9- ene), the parent alcohol of the family of acetylated scirpenol mycotoxins produced by several Fusarium species, has been implicated in mixed toxicoses of animals, but there is not a general description of its toxicity in chickens. Dietary STO (0, 2, 4, 8, 16, and 32 micrograms/g feed) was fed to four groups of 10 male day-old broiler chickens for 3 wk. The minimum effective dose (MED) for reducing growth rate significantly (P less than .05) was 4 micrograms/g. The same MED was found for increased serum alkaline phosphatase and relative weight of the gizzard. Unlike literature reports for two other trichothecene mycotoxins, T-2 toxin and diacetoxyscirpenol (DAS), STO impaired feed conversion efficiency but did not alter spleen or pancreas size. The MED of STO for decreases in serum lactic dehydrogenase and aspartate aminotransferase was 8 micrograms/g, but the MED for decreased serum albumin and total proteins and regression of the bursa of Fabricius was 16 micrograms/g. Serum sodium, potassium, and calcium were not altered at the highest dose, 32 micrograms/g, but serum phosphate, uric acid, and cholesterol were decreased by 32 micrograms/g. Serum chloride was increased slightly but significantly (P less than .05) at 16 and 32 micrograms/g. Based on these results, STO toxicosis of chickens can be differentiated from those of T-2 toxin and DAS and its toxicity appears sufficient to warrant further attention.

Mouth lesions in broiler chickens caused by scirpenol mycotoxins.

Dietary scirpentriol (STO), triacetoxyscirpenol (TAS), monoacetoxyscirpenol (MAS), and diacetoxyscirpenol (DAS), mycotoxins produced by Fusarium species, were compared for their ability to cause mouth lesions when graded dietary levels (0, 1, 2, 4, and 8 micrograms STO or TAS/g; 0, .5, 1, 2, and 4 micrograms MAS or DAS/g) were fed to male broiler chickens for 21 days after hatching. The mouth lesions provoked by each scirpenol were dose-related. The minimum effective doses (MED) were 4, 2, 1, and .5 micrograms/g for TAS, STO, DAS, and MAS, respectively, whether the number of affected birds or the number of affected mouth parts (angles, upper beak, lower beak, and tongue) was the measured response. Lesion sites in the mouth varied with the toxin. The rank orders from greatest to least affected sites were angles, upper beak, lower beak, and tongue for TAS and STO, upper beak, lower beak, angles, and tongue for MAS, and upper beak, lower beak, tongue, and angles for DAS. Mouth lesions were clearly visible with each toxin after feeding for 1 wk and the numbers of affected mouth parts almost tripled after 2 wk exposure. During Week 3 of exposure, only the increase caused by MAS was significant (P less than .05). The MED for growth inhibition were 2, 2, 2, and 8 micrograms/g for STO, MAS, DAS, and TAS, respectively. Thus, mouth lesions were of equal or greater sensitivity than growth inhibition as an indicator of scirpenol toxicity. It would appear that the discovery of mouth lesions in birds justifies a mold and mycotoxin control program.

Influence of degree of acetylation of scirpenol mycotoxins on feed refusal by chickens.

The refusal by young chickens of feed containing graded levels (0, 1.25, 2.5, 5.0, 10.0, 20.0, and 40.0 micrograms/g of diet) of the Fusarium mycotoxins scirpentriol (STO), monoacetoxyscirpenol (MAS), diacetoxyscirpenol (DAS), and triacetoxyscirpenol (TAS) was tested in a defined experimental model. The order of activity as measured by minimum effective dose was DAS greater than MAS = STO greater than TAS whereas the order measured by percentage refusal at 10, 20, and 40 micrograms/g was MAS greater than DAS greater than STO greater than TAS. These results imply that feed refusal associated with corn and feed infested with Fusarium sps. might be a multiple toxicosis because the scirpenols, which are not tested for routinely, can occur together naturally.

Toxic effects of aflatoxin B1 in chickens given feed contaminated with Aspergillus flavus and reduction of the toxicity by activated charcoal and some chemical agents.

Aspergillus flavus NRRL 3357 was grown on enriched long-grain rice for 7-10 days to produce aflatoxin B1 (AFB1). The quantity of AFB1 in moldy rice was determined by thin-layer chromatography using ultraviolet light. When the dried moldy rice powder was fed to day-old Hubbard X Hubbard broiler chicks in unmedicated feed (AFB1 level 10 ppm) for 8 weeks, there was a profound reduction in weight gain and feed consumption. Chickens fed AFB1 developed severe liver damage, as determined by the concentration of hepatic microsomal cytochrome P-450 and by the activities of microsomal benzphetamine N-demethylase and serum glutamic oxalacetic transaminase. However, activated charcoal, reduced glutathione, cysteine, selenium (as sodium selenite), beta-carotene, and fisetin administered orally considerably reduced the toxicity of AFB1 in the experimental chickens.

Efficacy of activated charcoal and other agents in the reduction of hepatotoxic effects of a single dose of aflatoxin B1 in chickens.

Liver injury caused by a toxic dose of aflatoxin B1 (AFB1) (6 mg/kg, p.o.) in experimental chickens was measured by observing changes in hepatic microsomal cytochrome P-450 and the activity of microsomal benzphetamine N-demethylase and serum glutamic oxaloacetic transaminase (SGOT). However, simultaneous administration of activated charcoal, reduced glutathione (GSH), cysteine, selenium, beta-carotene or fisetin with aflatoxin B1 considerably reduced the toxic injury to liver as measured by the above parameters.