Human & Experimental Toxicology

From 1987 to 1994, 31 cases of acute paraquat poisoning were managed in the CHRU of Pointe à Pitre (FWI). Eighteen patients died, 13 survived. Biological indexes accurately predicted patient's outcome in all cases out of one. In the last case biological parameters were mislead ing : the corresponding patient survived despite consistent clinical and biological prognosis of death. The unexpected survivor was West Indian, male, agricultural worker of 26 years who alleged drunk about 300 ml of gramoxone (20% v/v paraquat) in a suicide attempt. The patient was HIV infected (Elisa+, Western-Blot+) and presented an AIDS syndrome (CD4 count inferior to 200 cells/mm³) estab lished since 10 months and treated by AZT. We could not identify any other distinguishing features among the unexpected survivor and the rest of the patients. This observation suggests that the immunological status of the patient could explain this protection from paraquat toxicity

1 Rats were dosed orally with illudin S, a toxic substance derived from the poisonous mushroom Lampteromyces japonicus. The digestive tract showed severe damage, whereas the liver, kidney and lung did not show any significant changes.

2 The effects observed became more pronounced with increasing illudin S dose (5, 10 or 20 mg kg ^-1 body weight).

3 Severe inflammation and oedema were observed in the stomach and moderate changes in the proximal part of the small intestine.

4 Histopathological examination revealed haemorrha gic erosions and marked inflammatory oedema in the gastric mucosa.

1 Two separate cases of acute occupational poisoning following exposure to vapours of a fire extinguishing liquid are described. Analytical, clinical, pathological and toxicological data leave little doubt that toxicity was due, in both cases, to inhalation of carbon tetrachloride present at high concentrations (>15% and 78% by weight, respectively) in the fire extinguishing liquid.

2 Both subjects were admitted to hospital, 4 and 8 days after exposure, respectively, and developed severe hepato-nephrotoxicity with hepatomegaly, increased va lues of serum transaminases, blood urea nitrogen (BUN), creatinine, γ-glutamyl-transpeptidase (γ-GT), bilirubin and uric acid and, finally, anuria. They recovered in about three to four weeks, after several haemodialytic sessions.

3 Interestingly, in both cases the other workers exposed under the same conditions and for the same period of time as the two patients showed no signs or symptoms of toxicity. The reason for the observed different suscept ibility to CCl₄ is attributable to an abnormally high ethanol abuse by the two workers, as reported in the clinical records and confirmed by their relatives and collegues (120 and 250 g per day, respectively). Daily ethanol intake by the coworkers was less than 50 g for all subjects.

4 Although the potentiating effect of ethanol on the toxicity of CCl₄ is well known in experimental animals, as a result of cytochrome P-450 induction, direct evidence in humans reported in the literature so far was limited by the lack of information, in all published reports, on the presence or absence of effects in non-alcoholic exposed 'controls', when these were present.

Sister chromatid exchange (SCE) frequencies were deter mined in peripheral lymphocytes from traffic policemen drawn from various busy traffic points of Madras metro in India. These policemen were under constant exposure to automobile exhaust pollution during their 8 h work schedule. Analysis of SCE frequencies revealed a sig nificantly greater number of SCE/cell in these policemen as against the matched control population. Sixty percent of these subjects who remained in the service after 5 years showed insignificant but higher values of SCE than in the initial analysis.

The effects of low lead exposure were investigated in 98 children (7-12 years old) living and studying within a 1 km radius of a lead smelter (exposed population) located in Torreón, Coahuila, México, and compared with 30 children living and studying 4.5 km from the same smelter (control population). Both populations had similar socio- economic conditions. The exposed population showed higher blood lead (PbB) and free erythrocyte protopor phyrin (FEP) concentrations (17.3 ± 5.6 μg dl^-1 and 53.9 ± 46.1 μg μl^-1, respectively) than controls (PbB, 6.4 ± 3.1 μg dl^-1 and FEP,13.9 ± 7.3 μg di^-1). PbB concen trations were inversely correlated to distance from the smelter (r ² = 0.494). However, in the exposed population, wind direction also had a significant effect on the PbB and urinary lead (PbU) concentrations. The exposed popula tion was divided according to PbB into a high level lead group (PbB > 15 μg dl^-1), which also showed high FEP concentrations and a low lead group (PbB < 15 μg dl^-1). Clinically, the high lead group showed a greater incidence of general symptoms (colic, headache, paresthesia, myalgia and dizziness), impairment of some neuromus cular functions (neuromuscular conduction velocity and motor coordination) and a decrease of intelligence quotient (IQ), which was not related with sex or socio- economic status. These results are an evidence of morbidity in children with high PbB concentrations.

1 The morphological consequences of hypobaric hypox ia, exposure to reduced pressure atmospheres, were examined in the hippocampus of male Fischer 344 rats. Severe chronic hypoxia can produce permanent neuronal damage with hippocampal structures being especially vulnerable.

2 Hippocampal morphology was studied using histolo gical observations after a 4 day exposure to sea level, 5500 m, or 6400 m. Two groups tested at 6400 m were sacrificed at different intervals following exposure, 72 and 144 h, to examine the effect of post-exposure time on neuronal damage.

3 Histological damage was observed in rats' brains following exposure to altitude, with cell degeneration and death increasing as altitude increased. In addition, it was found that the longer the time following exposure before sacrifice, the more noticeable the damage, suggest ing delayed neurotoxicity. Increases in the number of damaged cells following altitude were significant for the CA3 region of one 6400 m group; however, other differ ences did not reach statistical significance. Rats exposed to altitude for 4 days ate less and lost significantly more weight than did animals at sea level.

4 It appears that 4 days of exposure to altitudes less than or equal to 6400 m does produce changes in the CA3 subfield, but the damage is different than that seen with other models of non-transient ischemia.

1 Anesthetized rats received the TCA desipramine (DMI) 60 mg kg^-1 i.p. Administration of the nitric oxide synthase (NOS) inhibitor N^G-nitro-L-arginine methyl ester-(L-NAME) 15 min after DMI reversed hypotension within 5 min (P < 0.05). In contrast to its beneficial effect on blood pressure, L-NAME worsened DMI-induced prolongation of the electrocardiographic QRS interval. Dexamethasone, an inhibitor of NOS induction, did not prevent DMI-induced hypotension.

2 To study the effect of L-NAME on survival, DMI was administered to anesthetized rats as a continuous i.v. infusion until death. Despite initially improving blood pressure, L-NAME decreased the mean survival time by 33% (P < 0.01) compared to control treatment. Adminis tration of the nitric oxide (NO) donor nitroglycerine to rats during DMI infusion likewise decreased the mean survival time.

3 L-NAME partially reversed the hypotensive effect of nitroprusside in both anesthetized and awake rats.

4 These data suggest that NO production attributable to constitutive NOS (cNOS) activity aggravates the hypoten sion associated with DMI toxicity in the anesthetized rat, and contributes to the pathophysiology of this overdose. The shortened survival time produced by both increasing and decreasing NO production suggests that cNOS activity during DMI overdose is regulated and adaptive. Ongoing cNOS activity also contributed to nitroprusside-induced hypotension, and may represent a feature common to other drug-induced hypotensive states.

1 Contrary to established metabolic pattern, a recent investigation of NNK metabolism produced in rat urine higher levels of 4-(methylnitrosamino)-1-(3-pyridyl)-1- butanone (NNK) and 4-(methylnitrosamino)-1-(3-pyri dyl)-1-butanol (NNAL) than their N-oxides, suggesting that reconversion of N-oxides could occur after urine formation.

2 To verify the possible role of bacteria in the reduction of NNK-N-oxide and NNAL-N-oxide to their respective parent compounds, NNK and NNAL, in smokers with urinary tract infection (UTI), the N-oxides were isolated from the urine of rats treated with [5-³H]NNK and individually incubated at 37°C with ten bacterial species in sterile human urine under different pH regimens. After incubation with the bacteria, aliquots of culture media were analyzed by high pressure liquid chromatography (HPLC) with radiochemical detection.

3 Escherichia coli, Enterobacter cloacae, Klebsiella pneumoniae and Proteus mirabilis possessed varying capacity to regenerate NNK and NNAL from their N- oxides while others showed no detectable reductive capability within 24 h.

4 This result constitutes the first experimental evidence that in tobacco users with concomitant UTI, bacterial regeneration of the procarcinogenic NNK and NNAL from their N-oxides could occur in the bladder leading to increased carcinogen burden in these individuals.

1 Phenytoin is a hydantoin-type anticonvulsive agent used extensively for nearly sixty years in the prophylactic treatment of grand mal and psychomotor seizures.

2 Based upon somewhat contentious evidence of pheny toin-induced lymphoma in mice and upon epidemiologic evidence of an association between anticonvulsive ther apy and lymphoma in epilepsy patients, the International Agency for Research on Cancer (IARC) has collectively regarded these data as limited evidence of carcinogeni city.

3 Two year carcinogenicity studies of standard bioassay design conducted in mice and rats yielded statistically significant increased incidence of hepatocellular adeno mas in mice at phenytoin plasma concentrations approx imating the therapeutic anticonvulsive range. Tumor incidence in rats was not affected. Previous carcinogeni city studies have found similar increases in hepatic tumor incidence in mice.

4 Phenytoin is a known enzyme inducer and shows tumor promoting activity in chemically initiated mouse liver. Evidence for genotoxicity is weak or equivocal, consequently phenytoin-induced liver tumors appear to occur through nongenotoxic mechanisms.

5 Finally, despite six decades of extensive therapeutic use and thorough epidemiologic evaluation, there is no evidence for an association between liver cancer and phenytoin therapy in epilepsy patients. Thus, hepatocel lular neoplasia in phenytoin-treated rodents appears to be of little significance to man.

Tetanus Toxoid loaded biodegradable microspheres (MTT) (poly (DL-Lactide-co-Glycolide) were administered intramuscularly to pregnant Wistar rats from Days 6 to 15 of gestation, at 1, 5 and 10-times the human equivalent dose of TT. Developmental defects in relation to soft tissues and skeleton, weight and sex of live pups and early fetal deaths from treated and control rats were analysed. The findings in treatment groups were comparable to those in the controls. These observations show that MTT was safe for pregnant rats and developing pups.

Nine new octadentate ligands based on cyclic, spermine (3,4,3-LI), desferrioxamine (DFO), or H-shaped tetrakis amine (penten) molecular backbones were prepared containing catecholamide (CAM), carboxycatecholamide (CAM(C)), or terephthalamide (TAM) chelating units. Mice were injected intravenously with ²³⁸Pu(IV) citrate, treated with 30 μmol kg^-1 of a ligand by intraperitoneal injection at 1 h or by gastric intubation at 3 min, and Pu retention in tissues and Pu transfer to excreta were measured at 24 h. Given by injection, three soluble ligands composed of MeTAM (3,4,3-LIMeTAM, DFO-MeTAM, H(2,2)-MeTAM) reduced Pu retention in the body to 27- 28% of control compared with 32 and 37% of control obtained in mice similarly treated with 3,4,3-LICAM(C) or CaNa₃-DTPA, respectively. The MeTAM ligands reduced Pu retention in the skeleton as much as an equimolar amount of CaNa ₃-DTPA, while Pu retention in the liver (on average, 16% of control) was significantly less than was obtained with CaNa₃-DTPA (35% of control). Given orally, H(2,2)-MeTAM reduced Pu retention in the whole body to 58% of control compared with reductions to 62 and 94% of control achieved with 3,4,3-LICAM(C) or CaNa₃-DTPA, respectively. Penten is both partially preorganized for metal binding and spatially suitable for encapsulation of actinide(IV), and ligands with the penten backbone are easier and less costly to prepare than those based on spermine or DFO. The biological results confirmed that penten is a suitable as well as practical structural backbone for new octadentate ligands. In agreement with the great stability of the ferric complex with MeTAM, as determined in vitro, the small, simple, soluble penten- based octadentate ligand, H(2,2)-MeTAM, was shown to be, overall, the most effective catecholamide ligand for enhancing Pu excretion. Either combined in H(2,2)- MeTAM or separately, the penten backbone and the MeTAM chelating unit are potentially useful additions to the set of backbones and binding units of multidentate ligands identified as effective for in vivo chelation of the actinides.