Rolf Hartung

Dose—Response Relationships

One of the most powerful tools in the analysis of toxicological events is the description of the intensity of the exposure in terms of dose, dose rate, or concentration for a specified duration of exposure in relation to the frequency or intensity of the observed responses. Dose-response relationships have received a generic treatment in all general textbooks of toxicology, such as those by Loomis (1974), Doull et al. (1980), and Hapke (1975). The statistical risk of experiencing an effect from an exposure to a chemical can be attributed to the interaction of several important factors. As noted in Chapter 1, this complex relationship of dose to response was already recognized as early as the 16th century by Paracelsus. To restate his observations as they apply in contemporary toxicology—a sufficiently high dose of any compound will produce severe adverse effects in all exposed organisms. Conversely, a sufficiently low dose of any compound will produce no significant effects that can be experimentally determined, no matter how sophisticated or extensive the experiment.

An updated evaluation of the carcinogenic potential of 1,4-dioxane

This paper presents a critical review of the information pertaining to the potential carcinogenicity of 1,4-dioxane. The primary target organs for cancer via the oral route are the liver and the nasal cavity, however, the relevance of nasal cavity tumors to human exposures has been questioned. Liver tumors were accompanied by degenerative changes and appear only to occur at high doses where clearance mechanisms are saturated and liver toxicity is significant. Genetic toxicity data suggests that 1,4-dioxane is a very weak genotoxin. An increase in hepatocyte cell proliferation was reported and 1,4-dioxane was shown to act as a tumor promoter in rat liver and mouse skin carcinogenicity assays. Two reports are available from the literature regarding physiologically based pharmacokinetic (PBPK) modeling approaches to assess the risk of liver cancer for 1,4-dioxane. A comparison of cancer risk estimates from linear and nonlinear models in the presence or absence of PBPK modeling suggests that USEPAs current cancer slope factor significantly overestimates the potential cancer risk from 1,4-dioxane. This critical review of the scientific literature indicates that a formal reevaluation of the carcinogenic potency of 1,4-dioxane is warranted.

NOVEL METHODS FOR THE ESTIMATION OF ACCEPTABLE DAILY INTAKE

This paper describes two general methods for estimating ADIs that circumvent some of the limitations inherent in current approaches. The first method is based on a graphic presentation of toxicity data and is also shown to be useful for estimating acceptable intakes for durations of toxicant exposure other than the entire lifetime. The second method uses dose-response or dose-effect data to calculate lower CLs on the dose rate associated with specified response or effect levels. These approaches should lead to firmer, better established ADIs through increased use of the entire spectrum of toxicity data.

The effect of diethanolamine on hepatic and renal phospholipid metabolism in the rat

Abstract DEA inhibited the in vitro synthesis of both phosphatidyl choline and phosphatidyl ethanolamine in liver tissue. In each case the K 1 was approximately 3 m m DEA. DEA inhibited the formation of phosphatidyl choline competitively, and produced a mixed type of inhibition for the synthesis of phosphatidyl ethanolamine. Administration of a single dose of 250 mg/kg DEA failed to produce inhibition of synthesis, but 330 mg/kg/day caused significant inhibition when given repeatedly. The most notable reduction of choline and ethanolamine incorporation occurred in the liver. The synthesis of ethnolamine phosphoglycerides declined to 27% of the control value after 1 week of DEA administration; no further reduction was seen during the remainder of the 3-week dosing regimen. Choline incorporation fell to 82% of the control value after 1 week, and to 47% and 41% after 2 and 3 weeks of DEA administration, respectively. The incorporation of these endogenous bases in renal tissue was also decreased. Ethanolamine phosphoglyceride synthesis declined steadily throughout the dosing regimen reaching a level 41% of control. Choline incorporation declined to 71% or control by the end of the third week. The kinetics of synthesis of the phospholipid derivatives of choline, ethanolamine, and DEA proved that the former two compounds were synthesized at a faster rate and in greater quantities. They were also catabolized at a slightly faster rate than the derivatives of DEA. The biological half-life of the phospholipid derivatives of DEA is longer than that of similar derivatives of choline and ethanolamine. This may favor accumulation of the DEA-containing phospholipid during chronic exposure.

Cholinesterase inhibition in the acute toxicity of alkyl-substituted 2-aminoethanols☆

Abstract The acute oral and intraperitoneal toxicity of a series of alkyl-substituted 2-aminoethanols was studied in relation to cholinesterase inhibition. All the 2-aminoethanols studied inhibited cholinesterase in vitro . The level of in vitro inhibition was related to the number of carbon atoms attached on the nitrogenous head of the 2-aminoethanol molecule. The median inhibitory concentrations correlate well with the LD 50 data. Intraperitoneal LD 50 doses of four alkyl-substituted 2-aminoethanols produced significant reductions in brain cholinesterase in rats.

Diethanolamine-induced alteration of hepatic mitochondrial function and structure

Abstract Diethanolamine (DEA) has been shown to interfere with phospholipid metabolism. It was hypothesized that DEA may alter membrane-bound biochemical processes which are dependent upon phospholipids. DEA was investigated for its effect on hepatic mitochondrial function and structure in the male Sprague-Dawley rat. DEA did not produce mitochondrial alterations in in vitro preparations from liver tissue. Similarly, acute treatment in vivo was without effect. However, a loss of mitochondrial integrity developed after subacute administration of DEA. Rats were given 0.25 (42 mg/kg/day), 1.0 (160 mg/kg/day), or 3.0 (490 mg/kg/day) mg/ml in their drinking water for varying periods up to 5 weeks. The effects on mitochondria were dose- and time dependent. Significant alterations appeared after 3 days at 3.0 mg/ml and after 1 week at 1.0 mg/ml. Mitochondrial State 4 activity was significantly elevated at all three dose levels following 2 weeks of DEA treatment. Concomitantly, an increase was noted in the Mg2+-dependent ATPase activity from rats treated with DEA at 2.0 mg/ml for 3 weeks. Electron micrographs indicated that treated animals had swollen hepatic mitochondria. The changes in the organelle may be related to alteration of phospholipid metabolism by DEA.

Biological Effects of Heavy Metal Pollutants in Water

I beg your indulgence if I begin my presentation with a brief review of toxicological principles. Toxicology covers the entire range of harmful interactions of chemical substances with the biota. This therefore expands the range from studying very acute effects down to the study of exceedingly subtle changes in behavior and function after long-term exposure for the determination of safety. The studies of functional deficits, carcinogenicity and teratogenicity are well established in toxicological investigations, at least for the safety evaluation of drugs, pesticides, and food additives for man. Studies on subtle behavioral changes and mutagenicity are gaining increasing acceptance. The types of measurements which have been noted most frequently for the study of heavy metals in water are lethality, growth, and reproduction. Behavioral changes and alterations in community structure are not normally investigated, even though they might have sizeable repercussions on the sustained survival of any species.

The Effects of Methoxychlor on Riffle Invertebrate Populations and Communities

Abstract A study was conducted to evaluate the chronic effects of a toxicant on interacting stream invertebrate populations. The study involved the continuous dosing of a small stream at 0.2 μg/liter methoxychlor for over one year. Invertebrate populations were monitored by artificial substrate and bottom sample collections of riffle invertebrates. Most invertebrate populations experienced some reduction due to the stream dosing. Some taxa (baetids and plecopterans) were affected as reflected by population reductions in dosed areas. Many taxa (hydropsychids, simulids, and aeschnids) were temporarily affected, experiencing initial population reductions in dosed areas but then recovering to control levels. Other taxa (chironomids and elmids) were not affected by the pesticide dosing. The riffle invertebrate community colonizing artificial substrates experienced a temporary decrease in diversity through both reduced richness and evenness. Diversity was not decreased in bottom sample collections. In general, ...

Effects of diethyltindichloride on amino acid and nucleoside transport in suspended rat thymocytes.

Effects of Diethyltindichloride on Amino Acid and Nucleoside Transport in Suspended Rat Thymocytes. MILLER, R. R., HARTUNG, R., AND CORNISH, H. H. (1980). Toxicol. Appl. Pharmacol. 55, 564-571. The effects of diethyltindichloride (DETD) on basic biochemical processes of thymus cells were investigated in order to develop an understanding of the mechanism by which dialkyltins act on the thymus of rodents in viva. Accumulation of the nonmetabohzable amino acid cu-aminoisobutyrate (AIB) was markedly inhibited by the dialkyhins in suspended rat thymocytes. The inhibitory effects on AIB influx were apparent after as little as 5 min of thymocyte preincubation with DETD. Low dialkyltin concentrations, which did not inhibit AIB influx in noninsulin-stimulated cells, abolished the insulin-mediated AIB influx. Addition of lipoic acid (reduced) to the incubation medium prevented the inhibi- tory action of DETD on AIB influx. DETD markedly inhibited labeled thymidine incorpora- tion into DNA of suspended rat thymocytes, possibly via inhibition of transmembrane trans- port of this nucleoside precursor. In sharp contrast to its effect on thymidine incorporation, DETD stimulated the incorporation of labeled uridine into RNA.

Convulsions induced by 2-N-di-n-butylaminoethanol☆

Abstract Dibutylaminoethanol (Bu 2 AE) produces convulsions in rats leading to respiratory arrest regardless of route of administration. The lethality of 5 × LD50 doses of Bu 2 AE can be readily overcome by artificial respiration for 2–4 hr. In vivo phrenic nerve-diaphragm preparations indicate that the respiratory arrest is due to a neuromuscular blockade. Spontaneous activity of the phrenic nerve increases during convulsions and persists during blockade. Pretreatment with mephenesin or diphenylhydantoin, but not pentobarbital, was effective in counteracting convulsions and respiratory arrest. Bu 2 AE has also been shown to be a moderate inhibitor of acetylcholinesterase. It is proposed that the increased nerve activity during convulsions with its simultaneous increase in acetylcholine release, acts in concert with the moderate level of cholinesterase inhibition, producing a neuromuscular blockade due to excessive acetylcholine accumulation at the junction.