Toxicity To Other Species Research Articles

International Consortium to Advance Cross-Species Extrapolation of the Effects of Chemicals in Regulatory Toxicology.

International Consortium to Advance Cross-Species Extrapolation of the Effects of Chemicals in Regulatory Toxicology.

Susceptibility ofSpodoptera frugiperda(Lepidoptera: Noctuidae) Field Populations to the Cry1FBacillus thuringiensisInsecticidal Protein

The fall armyworm, Spodoptera frugiperda (Smith & Abbot) (Lepidoptera: Noctuidae), is a polyphagous insect pest affecting multiple crops. Fall armyworm in corn is managed with insecticides and corn hybrids expressing insecticidal proteins derived from Bacillus thuringiensis Berliner (Bt). The early detection of insect resistance is important for making appropriate management decisions and for implementing integrated pest management and insect resistance management recommendations. The objective of this study was to estimate susceptibility of fall armyworm populations to the Cry1F Bt insecticidal protein, emphasizing collections from locations where fall armyworm overwinters in the U.S. Fall armyworm neonates were exposed to artificial diet treated with increasing Cry1F concentrations, and mortality and growth inhibition were evaluated after 7 d. Differences in Cry1F susceptibility between the most susceptible and the most tolerant field populations were 2- and 6-fold for 2012 and 2013, respectively. These results are consistent with other susceptibility studies of Bt toxicity in other species although reduced susceptibility in one population collected from Florida may suggest resistance development.

EVIDENCE OF LEAD EXPOSURE IN A FREE-RANGING POPULATION OF KEA (NESTOR NOTABILIS)

Kea (Nestor notabilis) are high country parrots endemic to New Zealand. The foraging behavior and inquisitive nature of Kea have led to incidences of foreign substance ingestion, including lead. Between April 2006 and November 2007, 38 Kea in Aoraki/Mount Cook National Park, New Zealand, were captured, and blood was sampled for blood lead analysis. All birds sampled had detectable blood lead with concentrations ranging from 0.028 mg/l to 3.43 mg/l (mean+/-SE, 0.428+/-0.581 mg/l). A retrospective analysis of necropsy reports and archived samples from 15 wild Kea from various South Island locations also was carried out. Seven of these birds (five from the Aoraki/Mount Cook area) died with clinical signs consistent with lead toxicosis and had liver and/or kidney lead levels reported to cause lead toxicity in other avian species. All seven of these birds also had lead inclusions (Ziehl-Neelson positive intranuclear inclusion bodies) in the renal tubular epithelial cells. These are considered diagnostic of lead toxicity in other species. This study showed that lead exposure is ubiquitous in the sampled population and may be an important contributing factor in Kea morbidity and mortality. As a result of these findings, lead abatement in areas frequented by Kea is being initiated.

Species and organ specificity of fumonisin-induced endothelial alterations: Potential role in porcine pulmonary edema

Fumonisins, mycotoxins that commonly contaminate corn, induce cardiovascular toxicity and pulmonary edema in pigs, leukoencephalomalacia in horses, and nephropathy in rats, rabbits, and lambs. The mechanisms of these species-specific target organ toxicoses are poorly understood. We have previously reported perinuclear accumulation of membranous material in pulmonary capillary endothelial cells of pigs fed fumonisin-containing culture material. We hypothesized that these endothelial accumulations may be important in the pathogenesis of fumonisin-induced pulmonary edema and target organ toxicity in other species. Both target and non-target tissues from fumonisin-exposed pigs, sheep, rabbits, and rats were examined ultrastructurally. Specifically, lung, liver, heart and kidney were examined. In agreement with our previous work (Gumprecht, L.A., Beasley, V.R., Weigel, R.M., Parker, H.M., Tumbleson, M.E., Bacon, C.W., Meredith, F.I., Haschek, W.M., 1998. Development of fumonisin-induced hepatotoxicity and pulmonary edema in orally dosed swine: morphological and biochemical parameters. Tox. Pathol. 26, 777–788), endothelial alterations were present in the pulmonary capillary endothelial cells of pigs fed fumonisin-containing culture material, but at doses that did not induce pulmonary edema, as well as in pigs injected intravenously with purified fumonisin B 1. These alterations were present only in the pulmonary capillary endothelium of pigs and not in other species. In addition, these endothelial alterations were not present in any other organ of pigs or other species examined. Thus, these endothelial alterations are induced by fumonisin B 1, but only in pulmonary capillary endothelium and only in pigs. Although evidence that these alterations play a role in fumonisin-induced pulmonary edema is limited, other endothelial functions may be affected by fumonisin treatment.

Functional assessment of pulmonary capillary surface area in the 2-mo-old lamb

We recently reported that measurements of the maximal velocity of pulmonary endothelial angiotensin-converting enzyme (Vmax) in vivo provide information regarding microvascular surface area in the developing lamb. To obviate any subtle influences of development on Vmax aside from simple increases in surface area, we correlated Vmax with postmortem stereological assessments of alveolar surface area in the relatively mature lung of the 2-mo-old lamb (n = 14). We attempted to increase the range of surface area beyond its normal variability by injecting nine of the lambs with bleomycin, an antineoplastic agent with significant pulmonary toxicity in other species. Vmax, measured shortly after birth and then weekly, increased monotonically in all lambs. Despite their wide dispersion, Vmax and the stereological determinations correlated strongly at 2 mo of age, confirming that Vmax is a robust indicator of the surface area of the air-blood barrier. There was no significant difference in either measurement between the control lambs and those treated with bleomycin, suggesting that the newborn lamb is resistant to the effect of this agent.

The human relevance of the renal tumor-inducing potential of d-limonene in male rats: Implications for risk assessment

The monoterpene d-limonene is a naturally occurring chemical which is the major component in oil of orange. Currently, d-limonene is widely used as a flavor and fragrance and is listed to be generally recognized as safe (GRAS) in food by the Food and Drug Administration (21 CFR 182.60 in the Code of Federal Regulations). Recently, however, d-limonene has been shown to cause a male rat-specific kidney toxicity referred to as hyaline droplet nephropathy. Furthermore, chronic exposure to d-limonene causes a significant incidence of renal tubular tumors exclusively in male rats. Although d-limonene is not carcinogenic in female rats or male and female mice given much higher dosages, the male rat-specific nephrocarcinogenicity of d-limonene may raise some concern regarding the safety of d-limonene for human consumption. A considerable body of scientific data has indicated that the renal toxicity of d-limonene results from the accumulation of a protein, α2u-globulin, in male rat kidney proximal tuble lysosomes. This protein is synthesized exclusively by adult male rats. Other species, including humans, synthesize proteins that share significant homology with α2u-globulin. However, none of these proteins, including the mouse equivalent of α2u-globulin, can produce this toxicity, indicating a unique specificity for α2u-globulin. With chronic exposure to d-limonene, the hyaline droplet nephropathy progresses and the kidney shows tubular cell necrosis, granular cast formation at the corticomedullary junction, and compensattor cell proliferation. Both d-limonene and cis-d-limonene-1,2-oxide (the major metabolite involved in this toxicity) are negative in in vitro mutagenicity screens. Therefore, the toxicity-related renal cell proliferation is believed to be integrally involved in the carcinogenicity of d-limonene as persistent elevations in renal cell proliferation may increase fixation of spontaneously altered DNA or serve to promote spontaneously initiated cells. The scientific data base demonstrates that the tumorigenic activity of d-limonene in male rats is not relevant to humans. The three major lines of evidence supporting the human safety of d-limonene are (1) the male rat specificity of the nephrotoxicity and carcinogenicity; (2) the pivotal role that α2u-globulin plays in the toxicity, as evidenced by the complete lack of toxicity in other species despite the presence of structurally similar proteins; and (3) the lack of genotoxicity of both d-limonene and d-limonene-1,2-oxide, supporting the concept of a nongenotoxic mechanism, namely, sustained renal cell proliferation. Collectively, the evidence that the renal effects of d-limonene are confined to male rats because of the unique presence of α2u-globulin is quite compelling. In this regard, d-limonene is readily distinguished from classical renal carcinogens and should, therefore, not be subjected to traditional interspecies extrapolation and quantitative risk assessment. As d-limonene shows no toxicity or carcinogenicity in female rats or male and female mice when administered over a lifetime, it is considered safe for human consumption.

Effects on mitochondrial metabolism in livers of guinea pigs after a single or repeated injection of As2O3.

Differences in the metabolite pattern were observed in previous experiments in guinea pig livers after a single injection or prolonged (5 days) treatment with AS2O3 (Reichl et al. 1988). To elucidate the underlying mechanism the effect of As2O3 on liver metabolism was therefore investigated. Male guinea pigs received either a single dose (s.d.) of As2O3 10 mg x kg-1 s.c. or repeated doses (r.d.) of 2.5 mg x kg-1b.i.d. on 5 consecutive days. One hour after the s.d. or 1 h and 16 h after the last injection in the r.d. groups the animals were sacrificed in anaesthesia. The livers were removed by freeze clamping for the determination of various metabolites. In the s.d. group a significant decrease in hydroxybutyrate, acetylCoA, adenosinemonophosphate and in the ratio of hydroxybutyrate/acetoacetate and an increase in pyruvate, citrate, malate, and adenosinetriphosphate were observed. A significant decrease in glycogen, pyruvate, alpha-ketoglutarate, acetylCoA, and acetoacetate and a significant increase in malate and in the ratios of lactate/pyruvate and hydroxybutyrate/acetoacetate were observed in the r.d.1-h group. In the r.d.16-h group a significant decrease in glycogen, pyruvate, lactate, and adenosinemonophosphate was found, but the values tended towards control values. The data are consistent with mechanisms of As2O3 toxicity in other species as PDH inhibition with consecutive citric acid cycle and gluconeogenesis inhibition and excessive carbohydrate depletion.

Oxygen diffusion in the trout retina

Oxygen tensions were measured in vivo within the different layers of the rainbow trout retina. Oxygen microelectrodes were advanced in 10 μm increments through the retinas and the P O 2 measured at each location. Mean retinal P O 2 ranged from 124 mm Hg at the retinal-vitreal interface to 281 mm Hg at the choriocapillaris. These data reaffirm that the cellular layers of the normal trout retina are continually exposed to supra-arterial oxygen tensions that are known to cause toxicity in other species. The intraretinal P O 2 gradient was mathematically characerized and results indicate that the in vivo oxygen profile can be described by a two-component exponential function. In order to gain a better understanding of oxygen delivery to the retina, the data were also subjected to an analysis based upon the classical equation for planar diffusion. The trout retina is an excellent model for studying oxygen diffusion in vivo since this tissue is supplied with oxygen from a single source, thereby simplifying the mathematical analysis. Calculations yielded values of 1·86 × 10 −5 and 0·58 × 10 −5 ml O 2 min −1 cm −1 atm −1 (at 9°C) for the Krogh permeation coefficient ( DS) for the photoreceptor region and the remaining neural retina, respectively.

Species dependent gentamicin pharmacokinetics and nephrotoxicity in the young horse

Gentamicin pharmacokinetics and nephrotoxic potential were evaluated in twelve 2 to 3 month-old horses. Whereas recent evidence in our clinic indicated that young horses may be especially susceptible to gentamicin nephrotoxicity, young rabbits and rats are usually resistant. Gentamicin (4.5 mg/kg) was given by rapid intravenous injection, Serum gentamicin concentrations over a 13-hour period were fitted to an open, two-compartment, pharmacokinetic model. Subsequently, the same horses were divided into groups of 3 horses each. Each group received 0, 2.2, 4.4 or 8.8 mg gentamicin/kg, intramuscularly, every 12 hours for 15 days. Renal function was monitored. Peak and trough gentamicin concentrations were monitored daily. Renal sections were collected for histopathologic and electron microscopic examination. The (mean ± SD) serum halflife was 194 ± 37 minutes, total body clearance (Cl B) was 1.65 ± 0.79 mL/min/kg and volume of distribution at steady state (Vd (ss)) was 30.6 ± 9.4 L/100 kg. Decreased renal function, as detected by elevated serum urea nitrogen or creatinine concentrations, was detected only in the two youngest foals (including animals in both the 4.4 and 8.8 mg/kg dose groups). The trough serum gentamicin concentrations of these 2 horses increased over time. These horses had the lowest Cl B and Vd (ss) in the intravenous study. Morphologic changes were seen in kidneys of all treated horses and were similar to those occurring with gentamicin toxicity in other species. Our results support the clinical impression that very young horses may be more susceptible than adult horses, and adults of other species, to gentamicin nephrotoxicity.

Paraquat tolerant and susceptible perennial ryegrasses: effects of paraquat treatment on carbon dioxide uptake and ultrastructure of photosynthetic cells

Abstract. Paraquat treatment of susceptible Lolium perenne seedlings (cultivar Kent Indigenous) rapidly inhibited CO2 uptake and after 1 h chloroplasts exhibited abnormal fusions of the thylakoid membranes. Further ultrastructural changes occurred within the chloroplasts until 8 h after treatment, when cytoplasmic damage also became evident. The localization of primary damage within the chloroplast differs from previous reports of paraquat toxicity in other species. Paraquat treatment of tolerant L. perenne seedlings (line PRP IX) resulted in little change in CO2 uptake and ultrastructural effects were generally confined to the gradual development of deposits in the chloroplast stroma. These observations are discussed in relation to the mechanism of action of the herbicide and the proposed mechanism of paraquat tolerance in L. perenne.

Species and strain differences in target organ alkylation and toxicity by 4-ipomeanol: Predictive value of covalent binding in studies of target organ toxicities by reactive metabolites

The organ specificities of the in vivo covalent binding of 4-ipomeanol were closely correlated with the patterns of organ-specific damage by 4-ipomeanol in several different animal species and strains. In all species tested, the lung was a major target for 4-ipomeanol covalent binding and toxicity. In the hamster and the mouse, 4-ipomeanol caused liver necrosis and kidney necrosis, respectively, in addition to pulmonary damage. Correspondingly, high levels of covalent binding of 4-ipomeanol occurred in these target organs in these species. These in vivo results, in addition to studies of the in vitro covalent binding of 4-ipomeanol in microsome preparations from the various target tissues, were consistent with the view that the organ-specific toxicities of 4-ipomeanol were caused by a highly reactive 4-ipomeanol metabolite(s) primarily produced in situ in the respective target tissues. The present results suggest that studies of both the in vivo and the in vitro covalent binding of 4-ipomeanol may have some utility in predicting the target organ specificity of 4-ipomeanol toxicity in other species. The present investigations also have identified some relevant new in vivo toxicity models for future studies of the relationships between the metabolism and the toxicity of 4-ipomeanol.

1181 BACTERIAL ENDOTOXIN PROTECTION FROM PULMONARY OXYGEN TOXICITY

We have discovered that treatment with small doses of bacterial lipopolysaccharide (endotoxin)(approx. 1/100th LD50) affords marked protection against O2-induced lung damage and lethality in adult rats exposed to hyperoxia. Whereas the untreated adult rat normally succumbs to 95+% O2 exposure after 72 hours(66/201= 30% survival) with survivors showing evidence of severe lung injury (pulmonary edema and/or hemorrhage), rats treated with daily i.p. doses of endotoxin exhibit tolerance to O2 lethality(265/274=97% survival) and lung damage (approx. 85% without evidence of pulmonary edema or hemorrhage). In addition to investigating possible mechanisms to explain the marked protective action of endotoxin treatment (↑lung antioxidant enzyme activity, p<.05; ↓ number of potentially detrimental alveolar macrophages, p<.05), preliminary attempts have been made to determine if endotoxin will offer similar protection from 02 toxicity in other species and other age animals. To date, endotoxin treatment appears to be protective only in the adult rat and rabbit(75% vs. 0% survival in 95+% 02). Initial experiments have been done in neonatal guinea pigs(55% vs. 13% survival, but only 18% free of lung pathology); neonatal hamsters(21% vs. 17% survival); and, adult mice(57% vs. 50% survival). Whether there is a true species(and/or age) specificity for endotoxin protection, or whether ideal dosage schedules in the other species have not yet been determined, remains to be resolved. (NIH# 1F 32 HL05415, GM 12675).

Pharmacological Studies of d-Tubocurarine and Other Curare Fractions

1. The head drop assay for curare potency is described in detail. The head drop dose falls within the range of 0.125 to 0.175 mg./kg. d-tubocurarine for the rabbit. 2. The toxicity in other species indicates that rats and guinea pigs are more sensitive, having an HD 50 of 0.075 and 0.035 mg/kg. respectively. 3. Neostigmine is a limited antagonist of curare since its is effective against just paralytic doses of d-tubocurarine but is ineffective against higher doses. 4. No change from normal in the degree of paralysis or duration of action of d-tubocurarine was noted in nephrectomized or hepatectomized rats and rabbits. This supports the view that the rest of the body can cope with paralytic doses of d-tubocurarine. 5. With minimum paralytic doses there is no change in blood pressure. As respiration fails the blood pressure falls. High doses cause a vasomotor collapse similar to shock; pressor drugs are partly effective against this vaso-depression. 6. EKG records of cats, dogs, and rats indicate no marked change in rate or in the P-QRST complex with large doses of d-tubocurarine. The relatively low cardiotoxic properties of d-tubocurarine were also ascertained in Straub and Langendorf heart preparations. 7. The EEG in unanesthetized rats, rabbits, and cats remained unchanged with 5 to 50 times the paralytic dose of curare given IV. No signs of central stimulation or depression were seen. 8. When curare is given intracisternally to rabbits it produces violent convulsions with doses of 0.1 mg./kg. 9. The importance of adequate positive artificial respiration preferably with the addition of oxygen, to eliminate effects due to anoxia is emphasized. 10. The possible clinical implications of these studies are discussed.