Jerry F. Stara

Regulatory history and experimental support of uncertainty (safety) factors

A synthesis of available literature on uncertainty (safety) factors which are used to estimate acceptable daily intakes (ADIs) for toxicants is presented. This synthesis reveals reasonable qualitative biological premises, as well as specific biological data that support both the use and choice of these factors. A suggestion is made in order to derive a range of ADI. Research needs in various areas of uncertainty are also identified.

Comparison of 115mcadmium retention in rats following different routes of administration

Abstract Whole body retention studies of 115m Cd were carried out on rats following four different routes of administration: oral, inhalation, intraperitoneal, and intravenous. The retention curve for each route of administration was divided into two components. The first component reflected the initial rapid clearance of 115m Cd primarily by the gastrointestinal tract and the second component indicated the absorption and turnover of 115m Cd. Extrapolation of the second component to the intercept gave initial absorption values of 93%, 91%, 41%, and 2.3% for intraperitoneal, intravenous, inhalation, and oral routes, respectively. Immediately after inhalation exposure, 9.7% of the total inhaled Cd was present in the lungs. The route of administration did not significantly influence the rate of elimination and biological half-life of the second component of the whole body retention curve.

Gastrointestinal absorption of different compounds of 115mcadmium and the effect of different concentrations in the rat

Abstract The absorption and retention of three different compounds of 115mcadmium and the effects of variations in concentration were studied in female rats. After a single oral dose, the chloride, sulfate, and acetate forms of 115mCd did not significantly influence the absorption, retention, or distribution of the 115mCd in the tissues. The only organs containing significant amounts of 115mCd were the liver, kidney, and gastrointestinal tract. Increases in concentration of cadmium resulted in more cadmium being absorbed from the gastrointestinal tract, although the amount absorbed was not proportional to the increase in concentration.

Whole body retention in rats of different 191Pt compounds following inhalation exposure.

The whole body retention, excretion, lung clearance, distribution, and concentration of 191Pt in other tissues was determined in rats following a single inhalation exposure to different chemical forms of 191Pt. The chemical forms of 191Pt used in study were 191PtCl4, 191Pt(SO4)2, 191PtO, and 191Pt metal. Immediately after exposure most of the 191Pt was found in the gastrointestinal and respiratory tract. Movement of the 191Pt through the gastrointestinal tract was rapid, most of the 191Pt being eliminated within 24 hr after exposure. Lung clearance was much slower, with a clearance half-time of about 8 days. In addition to the lungs, kidney and bone contained the highest concentrations of 191Pt.

Oral toxicity of methylcyclopentadienyl manganese tricarbonyl (MMT) in rats

Abstract Rats were given a single oral dose of MMT diluted in Wesson Oil. Eight groups of animals were used and the dosages varied from 15 to 150 mg/kg body weight. Necropsies were performed and tissues were taken for histopathological and Mn determinations from animals dying during the study and from a selected number of animals euthanatized at the end of the study. The LD 50 14 was 58 mg MMT/kg body weight. Histopathological changes were found in the lungs, liver and kidney. The severity of the changes was related to the dose. Concentrations of Mn in selected tissues were elevated in animals dying from exposure. At 14 days post ingestion, the Mn concentrations had fallen to approximately normal values.

Biological fate of a single administration of 191Pt in rats following different routes of exposure.

Abstract The retention, tissue distribution, and excretion of 191 Pt in adult rats was determined following oral, intravenous (IV), and intratracheal administration. The highest retention was obtained following IV dosing, and lowest retention (less than 0.5%) occurred after oral dosing. Tissues containing the highest concentrations of 191 Pt following IV administration were the kidney, adrenal, spleen, and liver. Following a single oral dose, almost all of the 191 Pt was excreted in the feces due to nonabsorption, whereas after IV dosing, similar quantities were excreted in both the urine and feces. Following IV dosing of pregnant rats, 191 Pt was found in all the fetuses; however, the amount was small.

Pentachlorophenol: Health and Environmental Effects Profile:

Pentachlorophenol is used as an industrial wood preservative for utility poles, crossarms, fence posts, and other purposes (79%);for NaPCP (12%); and miscellaneous, including mill uses, consumer wood preserving formulations and herbicide intermediate (9%) (CMR, 1980). As a wood preservative, pentachlorophenol acts as both a fungicide and insecticide (Freiter, 1978). The miscellaneous mill uses primarily involve the application of pentachlorophenol as a slime reducer in paper and pulp milling and may constitute ∼6% of the total annual consumption of pentachlorophenol (Crosby et al., 1981). Sodium pentachlorophenate (NaPCP) is also used as an antifungal and antibacterial agent (Freiter, 1978). Pentachlorophenol also is used as a general herbicide (Martin and Worthing, 1977). Photolysis and microbial degradation are the important chemical removal mechanisms for pentachlorophenol in water. In surface waters, pentachlorophenol photolyzes rapidly (ECETOC, 1984; Wong and Crosby. 1981; Zepp et al., 1984); however, the photolytic rate decreases as the depth in water increases (Pignatello et al., 1983). Pentachlorophenol is readily biodegradable in the presence of accli-mated microorganisms; however, biodegradation in natural waters requires the presence of microbes that can become acclimated. A natural river water that had been receiving domestic and industrial effluents significantly biodegraded pentachlorophenol after a 15-day lag period, while an unpolluted natural river water was unable to biodegrade the compound (Banerjee et al., 1984). Even though pentachlorophenol is in ionized form in natural waters, sorption to organic particulate matter and sediments can occur (Schellenberg et al., 1984), with desorption contributing as a continuing source of pollution in a contaminated environment (Pierce and Victor, 1978). Experimentally determined BCFs have shown that pentachlorophenol can significantly accumulate in aquatic organisms (Gluth et al., 1985; Butte et al., 1985; Statham et al., 1976; Veith et al., 1979a,b; Ernst and Weber, 1978), which is consistent with its widespread detection in fish and other organisms. Direct photolysis may be an important environmental sink for pen tachlorophenol present in the atmosphere. The detection of pen tachlorophenol in snow and rain water (Paasivirta et al., 1985; Bevenue et al., 1972) suggests that removal from air by dissolution is possible. Soil degradation studies indicate that pentachlorophenol is biodegrad able; microbial decomposition is an important and potentially domin ant removal mechanism in soil (Baker et al., 1980; Baker and Mayfield, 1980; Edgehill and Finn, 1983; Kirsch and Etzel, 1973; Ahlborg and Thunberg, 1980). The degree to which pentachlorophenol leaches in soil is dependent on the type of soil. In soils of neutral pH, leaching may be significant, but in acidic soils, adsorption to soil generally increases (Callahan et al. , 1979; Sanborn et al. , 1977). The ionized form of pentachlorophenol may be susceptible to adsorption in some soils (Schellenberg et al., 1984). In laboratory soils, pen tachlorophenol decomposes faster in soils of high organic content as compared with low organic content, and faster when moisture content is high and the temperature is conducive to microbial activity. Half- lives are usually ∼2-4 weeks (Crosby et al., 1981). Monitoring studies have confirmed the widespread occurrence of pentachlorophenol in surface waters, groundwater, drinking water and industrial effluents (see Table 2). The U.S. EPAs National Urban Runoff Program and National Organic Monitoring Survey reported frequent detections in storm water runoff and public water supplies (Cole et al., 1984; Mello, 1978). Primary sources by which pen tachlorophenol may be emitted to environmental waters may be through its use in wood preservation and the associated effluents and its pesticidal applications. Pentachlorophenol can be emitted to the atmosphere by evaporation from treated wood or water surfaces, by releases from cooling towers using pentachlorophenol biocides or by incineration of treated wood (Skow et al., 1980; Crosby et al., 1981). Pentachlorophenol has been detected in ambient atmospheres (Caut reels et al., 1977), in snow and rain water (Paasivirta et al,. 1985; Bevenue et al., 1972) and in emissions from hazardous waste incinera tion (Oberg et al., 1985). The U.S. Food and Drug Administrations Total Diet Study (conducted between 1964 and 1977) found pen tachlorophenol residues in 91/4428 ready-to-eat food composites (See Tables 4 and 5). The average American dietary intake of pen tachlorophenol during 1965-1969 was estimated to range from <0.001-0.006 mg/day (Duggan and Corneliussen, 1972). The most likely source of pentachlorophenol contamination in many food prod ucts may be the exposure of the food to pentachlorophenol-treated wood materials such as storage containers (Dougherty, 1978). Acute toxicity data indicated that salmonids are more sensitive to the toxic effects of pentachlorophenol than other fish species, with LC50 values of 34-128 μg/l for salmonids and 60-600 μg/l for other species. More recent data showed that carp larvae, bluegills, channel catfish and knifefish also had LC50 values < 100 μ gl (see Table 10). The most sensitive marine fishes were pinfish larvae, the goby, Gobius minutus, and eggs and larvae of the flounder, Pleuronectes platessa, all with LC50 values <100 μ g/l (Adema and Vink, 1981). The most sensitive freshwater invertebrate species were the chironomid, Chironomus gr. thummi (Slooff, 1983) and the snail, Lymnaea luteola (Gupta et al., 1984). The most sensitive marine invertebrates were the Eastern oyster (Borthwick and Schimmel, 1978), larvae of the crusta ceans, Crangon crangon and Palaemon elegans (VanDijk et al. , 1977), and the copepod, Pseudodiaptomus coronatus (Hauch et al., 1980), all with LC50 values <200 μg/l. In chronic toxicity tests, the lowest concentration reported to cause adverse effects was 1.8 μg/l (NaPCP), which inhibited growth of sockeye salmon (Webb and Brett, 1973). The marine species tested displayed similar thresholds for chronic toxicity. Both acute and chronic toxicity increased at lower pH, probably because a lower pH favors the un-ionized form of pentachlorophenol, which is taken up more readily and is therefore more toxic than ionized pentachlorophenol (Kobayashi and Kishino, 1980; Spehar et al., 1985). Data concerning the effects of pentachlorophenol on aquatic plants were highly variable. Therefore, it was difficult to draw conclusions from these data. Pentachlorophenol did not appear to bioaccumulate in aquatic or ganisms to very high concentrations. BCFs for pentachlorophenol were <1000 for most species tested. The highest BCF was 3830 for the polychaete, Lanice conchilega (Ernst, 1979). Some species appear to have an inducible pentachlorophenol-detoxification mechanism, as evidenced in several experiments in which pentachlorophenol tissue levels peaked in 4-8 days and declined thereafter despite continued exposure (Pruitt et al., 1977; Trujillo et al., 1982). A study by Niimi and Cho (1983) indicated that uptake of waterborne pentachlorophenol from gills was much greater than uptake from food, indicating that bioconcentration of pentachlorophenol through the food chain is unlikely. Biomonitoring data of Lake Ontario fishes showed that similar pentachlorophenol levels were found in predators andforage species. Studies with experimental ecosystems have indicated that ecological effects may occur at pentachlorophenol levels as low as those causing chronic toxicity in sensitive species in single-species tests. The lowest concentration that caused adverse effects in these studies was 15.8 μg/l, which caused a reduction in numbers of individuals and species in a marine benthic community (Tagatz et al., 1978). Pentachlorophenol is readily absorbed from the gastrointestinal tract of rats, mice, monkeys and humans (Braun et al. , 1977, 1978; Ahlborg et al., 1974; Braun and Sauerhoff, 1976). Peak plasma concentrations are reached within 12-24 hours after oral administration to monkeys (Braun and Sauerhoff, 1976), but 4-6 hours after oral administration to rats (Braun et al., 1977). After oral administration, the highest concentration of radioactivity was found in the liver and gastrointesti nal tract of monkeys (Braun et al., 1977). In rats and mice, tet rachlorohydroquinone was identified in the urine (Jakobson and Yllner, 1971; Braun et al., 1977; Ahlborg et al., 1974) as well as unmetabolized pentachlorophenol and glucuronide-conjugated pen tachlorophenol. Although Ahlborg et al. (1974) reported that oxidative dechlorination of pentachlorophenol occurs in humans, as evidenced by the presence of tetrachlorohydroquinone in the urine of workers occupationally exposed (probably by inhalation), analysis of human urine after ingestion of pentachlorophenol revealed the presence of conjugated pentachlorophenol and unmetabolized pentachlorophenol (Braun et al., 1978). The primary route of excretion after oral administrtation of all species studied is in the urine (Braun et al. , 1977, 1978; Ahlborg et al., 1974; Larsen et al., 1972; Braun and Sauerhoff, 1976). Although urinary excretion followed second-order kinetics in rats (Larsen et al., 1972; Braun et al., 1977) except in females receiving a single high dose (100 mg/kg) of pentachlorophenol, urinary excretion of pentachlorophenol in humans and monkeys followed first-order kinetics (Braun and Sauerhoff, 1976; Braun et al., 1978). Enterohepatic circulation played an importation role in the pharmacokinetics of pen tachlorophenol. The half-life of pentachlorophenol in the plasma is longer in female rats and monkeys than it is in male rats and monkeys (Braun et al. , 1978; Braun and Sauerhoff, 1976). Because many preparations of pentachlorophenol are contaminated with small but measurable amounts of highly toxic substances, such as dibenzodioxins, special

Fucoidan: Its Binding of Lead and Other Metals

Lead in its ionized form is a hazard to the body, therefore, rapid conversion of lead into a non-ionized form is of prime importance in the treatment of lead poisoning. Lead poisoning has normally been treated with chelating agents such äs ethylene-diamine-tetraacetic acid (EDTA) and penicillamine (PCA). These chelating agents are indeed highly effective in treatment ofacute lead poisoning. However, they have not been proven so in the treatment of chronic cases, or in the maintainance of low blood-lead levels among workers who are continuously exposed to lead. The use of PCA assists in the mobilization of lead, however, large doses are required and it also causes an excessive elimination of copper (Mj^sser and Bessman 1960); thereby decreasing its potential usefulness in lead poisoning. EDTA, a synthetic polyaminoacid has proved more promising in the alleviation of metal poisoning, although it too binds other metal ions besides those which require elimination from the body. Also, it does not give prompt relief of lead colic (Belknap and Perry 1954) and it is potentially nephiotonic and thus an overdose or prolonged treatment can cause nephrosis, which may or may not clear after therapy is discontinued.

Long-Term Exposure to Auto Exhaust and Other Pollutant Mixtures

Beagles were exposed 16 hours daily for 61 months to raw and photochemically reacted auto exhaust, oxides of nitrogen and sulfur, alone and in combination. Exposure to oxides of nitrogen reduced diffusion capacity and peak expiratory flow. Raw exhaust and raw exhaust plus oxides of sulfur produced pulmonary hyperinflation. Irradiated auto exhaust, alone and in combination with oxides of sulfur, produced increased expiratory resistance. Irradiated auto exhaust also impaired ventilatory distribution. Lung volumes, compliances, and maximum breathing capacity were not impaired by the experimental atmospheres. Such chronic pulmonary changes resulting from long-term, low-level exposure to ubiquitous urban air pollutants denote potential, serious adverse health hazards.

Dermal irritancy of metal compounds. Studies with palladium, platinum, lead, and manganese compounds.

Dermal irritancy of 14 materials, including several compounds of palladium, platinum and lead, and methylcyclopentadienyl manganese tricarbonyl, plus deionized water (negative control) and glacial acetic acid (positive control), was tested on male albino rabbits weighing 2 to 3 kg. Procedures and evaluation criteria were adopted from those in use by the National Institute for Occupational Safety and Health. Five materials were evaluated as unsafe for intact or abraded skin contact as judged by severity of responses: glacial acetic acid (C3H5PDCl)2, (NH4)2PdCl4, (NH4)2PdCl6, and PtCl4; one as safe for intact, but not for abraded, skin: K2PdCl6; and two as safe for intact skin but not for abraded skin unless protected: K2PdCl4 and PdCl2. The remainder were evaluated as safe for intact or abraded skin contact (irritancy grade less than 1 on a scale of 4): H2O, Pd(NH3)2Cl2, PdO, PtO2, PtCl2, PbCl2, PbO, MMT.