Chemical components, antioxidant potential and hepatoprotective effects of Artemisia campestris essential oil against deltamethrin-induced genotoxicity and oxidative damage in rats.

In the present study, we evaluated the antioxidant potential of Artemisia campestris essential oil (ACEO) and the possible protective effects against deltamethrin induced hepatic toxic effects. The ACEO showed radical scavenging activity with IC50 = 47.66 ± 2.51 µg/ml, ferric reducing antioxidant power (FRAP) potential (EC50 = 5.36 ± 0.77 µg/ml), superoxide scavenging activity (IC50 = 0.175 ± 0.007 µg/ml) and ˙OH scavenging activity (IC50 = 0.034 ± 0.007 µg/ml). The obtained results of phenolic profile demonstrated that phenolic compounds are the major contributor to the antioxidant activity of ACEO. GC-MS analysis revealed the presence of 61 components in which monoterpene hydrocarbons constitute the major fraction (38.85%). In in vivo study, deltamethrin exposure caused an increase of serum AST, ALT and ALP activities, hepatic malondialdehyde (MDA) (measured as TBARS) and conjugated dienes markers of lipid peroxidation (LPO), while antioxidant enzyme activities (SOD, CAT and GPx) decreased significantly. Furthermore, it induces DNA damage as indicated by DNA fragmentation accompanied with severe histological changes in the liver tissues. The treatment with vitamin E or ACEO significantly improved the hepatic toxicity induced by deltamethrin. It can be concluded that vitamin E and ACEO are able to improve the hepatic oxidative damage induced by deltamethrin. Therefore, ACEO is an important product in reducing the toxic effects of deltamethrin.

Severe cyanide poisoning from an alternative medicine treatment with amygdalin and apricot kernels in a 4-year-old child.

BACKGROUND: The use of complementary and alternative medicine (CAM) is widespread in children with cancer and is poorly regulated. PATIENTS AND METHODS: Case report. RESULTS: We describe a case of severe cyanide poisoning arising from CAM use. A severely agitated, encephalopathic, unresponsive 4-year-old boy (initial Glasgow Coma Scale of 3) with a history of metastatic ependymoma was brought to our emergency department by ambulance services. Initial blood gas analysis demonstrated severe metabolic/lactic acidosis. On detailed questioning of the parents, the use of CAM including intravenous and oral "vitamin B 17" (amygdalin) and oral apricot kernel was reported. After administering sodium thiosulfate, rapid improvement in his medical condition with complete recovery without need for further intensive care treatment was seen. Serum cyanide level was markedly elevated. CONCLUSIONS: Cyanide poisoning can be the cause of severe encephalopathy in children receiving CAM treatment with substances containing cyanogenic glycosides.

Effectiveness of wetting method for control of konzo and reduction of cyanide poisoning by removal of cyanogens from cassava flour.

BACKGROUND: Konzo is an irreversible paralysis of the legs that occurs mainly among children and young women in remote villages in tropical Africa and is associated with a monotonous diet of bitter cassava. Konzo was discovered in 1938 by Dr. G. Trolli in the Democratic Republic of Congo (DRC). It also occurs in Mozambique, Tanzania, Cameroon, Central African Republic, and Angola. It was first controlled in Kay Kalenge village, DRC, in 2011 with the use of a wetting method to remove cyanogens from cassava flour. Fourteen months later, another visit was made to Kay Kalenge. OBJECTIVE: To determine whether Kay Kalenge women were still using the wetting method, whether there were new cases of konzo, and whether the wetting method had spread to other villages. METHODS: Meetings were held with chiefs, leaders, and heads of mothers' groups, women from 30 households were interviewed, and three nearby villages were visited. Total cyanide and thiocyanate were analyzed in cassava flour and urine samples, respectively. RESULTS: The women in Kay Kalenge village still used the wetting method. There were no new cases of konzo. The mean cyanide content of the flour samples was 9 ppm, and no child had a mean urinary thiocyanate content greater than 350 micromol/L. The use of the wetting method had spread naturally to three adjacent villages. CONCLUSIONS: The wetting method has been readily accepted by rural women as a simple and useful method to control konzo by removing cyanide from cassava flour, and its use has spread to nearby villages. The wetting method should be promoted by health authorities to control konzo and reduce cyanide poisoning from high-cyanide cassava flour.

[Distribution of deltamethrin in acute poisoned rats].

OBJECTIVE: To establish an animal model in acute poisoned rat by deltamethrin and an analysis method for determination of deltamethrin by gas chromatography-electron capture detector (GC-ECD) and to study the distribution of deltamethrin in rats in order to provide the references for forensic medicine identification about such cases. METHODS: Rats were administered with deltamethrin of different doses(512 and 1,024 mg/kg) and killed 1.5 h later to be dissected rapidly for tissues (blood, hearts, livers, lungs, kidneys and brains etc.). Samples were dehydrated by anhydrous sodium sulfate and extracted with petroleum ether and acetone (V:V=4:1). The level of deltamethrin was determined by GC-ECD. RESULTS: There was a good separate between deltamethrin and endogenous impurities. The limit of quantification for deltamethrin in blood and liver were 0.1 microg/mL and 0.1 microg/g (S/N> or =10), respectively. The recovery rate of deltamethrin in blood was 91.55%-134.37% and both inter-day and intra-day precisions were less than 5.67%. The distribution of deltamethrin in poisoned rats with 512 mg/kg was as follow: lungs > livers > hearts > kidneys > blood > brains and with 1 024 mg/kg dose was lungs > blood > hearts > kidneys > brains > livers (P<0.05). CONCLUSION: The GC-ECD method is sensitive for determination of deltamethrin. The distribution of deltamethrin in rats has a dose-dependent manner. The study suggests that samples of blood, hearts, livers, lungs, kidneys and brains are suitable for deltamethrin poisoned analysis.

Oral deltamethrin ingestion due in a suicide attempt.

Deltamethrin intoxication is uncommon throughout the world. The toxicity of insecticides containing pyrethroids is considered relatively lower than that of other insecticides such as compounds containing organophosphate. Acute deltamethrin poisoning due to oral ingestions is relatively rare. This report describes a case of a 32-year-old woman admitted to the emergency department (ED) with irritability, muscle cramps, discomfort, sensation of burning, loss of sensation in her feet and arms and dyspnea due to deltamethrin ingestion. Deltamethrin intoxication should be considered as a differential diagnosis in patients presented to ED with nonspecific neurological symptoms. The supportive treatment in acute phase of intoxication is critical in the management of these patients since higher doses of deltamethrin ingestion may cause severe symptoms (Tab. 2, Ref. 16). Full Text (Free, PDF) www.bmj.sk.

[Intervention effect of dimercaptopropansulfonate sodium on central toxic induced by bromoxynil in vivo].

OBJECTIVE: to investigate the changes of γ-aminobutyric acid (GABA) and glutamate (Glu) in the cerebral cortex following acute bromoxynil intoxication in mice and the protective effect of sodium dimercaptopropane sulfonate (Na-DMPS). METHODS: 30 ICR mice were randomly divided into blank control group (10), exposure group (10) and Na-DMPS protection group (10). The levels of GABA and Glu in the cerebral cortex were measured by RP-HPLC. The glutamine (Gln) level and the glutamine synthetase (GS), glutamate decarboxylation enzyme (GAD), γ-aminobutyric acid transaminase (GABA-T) activity in the cerebral cortex were determined by UV colorimetric. RESULTS: compared with the control group [GABA: (3.41 ± 0.12) micromol/g, Glu (14.00 ± 0.16) micromol/g, Gln (1.25 ± 0.19) micromol/g, GAD (13.50 ± 0.25) micromol × g(-1) × h(-1), GABA-T (25.51 ± 0.21) micromol × g(-1) × h(-1), GS(142.19 ± 1.31) U/mg pro], the level of GABA [(3.14 ± 0.14) micromol/g] was decreased (P < 0.05), whereas the level of Glu [(17.54 ± 0.40) micromol/g] and Gln [(3.35 ± 0.27) micromol/g] were increased (P < 0.05), the activity of GAD [(11.93 ± 0.15 micromol × g(-1) × h(-1)], GABA-T [(24.15 ± 0.22) micromol × g(-1) × h(-1)], GS [(140.75 ± 1.01) U/mg pro] was decreased (P < 0.05) in acute intoxication group; Compared with the acute intoxication group, the level of GABA [(3.52 ± 0.30) micromol/g] was increased (P < 0.05), whereas the level of Glu [(14.20 ± 0.32) micromol/g] and Gln [(1.32 ± 0.17) micromol/g] were decreased (P < 0.05), the activity of GAD [(13.01 ± 0.45 micromol × g(-1) × h(-1)], GABA-T [(25.19 ± 0.26) micromol × g(-1) × h(-1), GS [(142.35 ± 1.20) U/mg pro] was increased (P < 0.05); In contrast, the levels of GABA, Glu, Gln and the activity of GAD, GABA-T, and GS in Na-DMPS protection group were not significantly different in comparison with control group (P > 0.05). CONCLUSION: the central toxic effects of mice with acute bromoxynil intoxication may be related to the changes of GABA and Glu content in the cerebral cortex;Na-DMPS can protect mice from bromoxynil-induced central toxic effects and GABA and Glu abnormal change in the cerebral cortex.

Synthesis and biological evaluation of novel pyrimidine-5-carbonitriles featuring morpholine moiety as antitumor agents.

Aim: Design and synthesis of novel morpholinopyrimidine-5-carbonitriles as antitumor agents. Materials & methods: New series of morpholinopyrimidine-5-carbonitriles have been synthesized. 19 derivatives (3b, 4a, 5-6, 9-12, 13a-e, 14a-c and 15-17) were evaluated for their in vitro antitumor activity by the National Cancer Institute (NCI; MD, USA). Moreover, compound 13e was evaluated against PI3K (α, ß and δ) and the mechanism of its cytotoxic activity on leukemia SR was studied. Results: Compound 13e possessed remarkable broad spectrum antitumor activity with GI50 (median growth inhibition) and TGI (total growth inhibition) values of 6.15 and 28.66 µM, respectively, caused cell cycle arrest at G2-M phase and significant increase in the percentage of annexin V-FITC - positive apoptotic cells, also increased the level of active caspase-3. Moreover, 13e revealed good safety profile against transformed human liver epithelial-2 (THLE2).

Application of the industrial hygiene hierarchy of controls to prioritize and promote safer methods of pest control: a case study.

In 2005, the California Department of Public Health, Occupational Health Branch (OHB) investigated an incident of pesticide exposure and identified 27 vineyard workers who became ill due to drift of cyfluthrin, a pesticide being applied to a neighboring orange field to control katydids. Another pest, citrus thrips, was also present in the field. We investigated safer alternatives for katydid and thrips control to prevent illness due to pesticide exposure and used the industrial hygiene hierarchy of controls to prioritize the control methods. OHB evaluated factors that contributed to pesticide exposure and identified safer alternatives by conducting literature reviews on katydid and thrips control, drift prevention technology, and other relevant topics, and by interviewing integrated pest management advisors, conventional and organic growers, equipment manufacturers, county agricultural commissioners, pest control advisors, regulatory agencies, and others. We prioritized methods using the industrial hygiene hierarchy of controls. We identified safer pest control practices that incorporated hazard elimination, chemical substitution, engineering controls, and administrative controls, including employer policies and government regulations.

Metabonomic investigations into the global biochemical sequelae of exposure to the pancreatic toxin 1-cyano-2-hydroxy-3-butene in the rat.

The time-related metabolic effects of 1-cyano-2-hydroxy-3-butene (CHB, crambene), a naturally occurring nitrile and experimental model toxin causing exocrine pancreatitis, have been investigated in rats using high-resolution NMR spectroscopy of urine and serum in combination with pattern recognition analysis. Rats were administered CHB subcutaneously in two doses, 15 mg/kg dose (n = 10) and 150 mg/kg (n = 10), and conventional histopathology and clinical chemistry assessments were performed. Urine samples were collected at - 16 and 0, 8, 24, 48, 72, 96, 120, 144 and 168 h postdosing and serum samples were collected at 48 and 168 h postdosing; these were analyzed using a range of 1D and 2D NMR spectroscopic methods. The metabolic profile perturbations seen throughout the time-course of the study are described, and the application of the spectral correlation technique Statistical TOtal Correlation SpectroscopY (STOCSY) to detect both structural and novel toxicological connectivities between xenobiotic and endogenous metabolite signals is illustrated for the first time. As a result, it is suggested that the STOCSY approach may be of wider application in the identification of toxic versus nontoxic metabolites in drug metabolism studies.

2-Methyl-4-chlorophenoxyacetic acid (MCPA) and bromoxynil herbicide ingestion.

CONTEXT: Ingestion of bromoxynil and 2-methyl-4-chlorophenoxyacetic acid (MCPA) in combination is associated with high mortality. Toxicity is characterised by hyperthermia and metabolic acidosis. Dialysis is a proposed treatment, but little data exist regarding its effectiveness. CASE DETAILS: Case 1: A 50-year-old female presented 18 h post-ingestion of 200 mL of bromoxynil(200 g/L) and MCPA(200 g/L). She was agitated, tachycardic and tachypnoeic. She was intubated and continuous venovenous haemodiafiltration (CVVHDF) was commenced. She deteriorated, becoming hypotensive, hyperthermic (39.5 °C) and hypercapnic (80 mmHg). She was cooled, paralysed, received CVVHDF for 2d and was extubated on day 4 making a full recovery. Case 2: A 60-year-old male presented 6 h post-ingestion of an unknown amount of bromoxynil (200 g/L) and MCPA (200 g/L). On arrival, he was tachycardic and tachypneic (pCO2 25 mmHg). At 8h post-ingestion he became hyperthermic, hypercapnic and acidotic (pH 7.15), and was intubated, paralysed, cooled and received CVVHDF for 36 h. He was extubated after 42 h and made a full recovery. Bromoxynil and MCPA serum and effluent concentrations were measured. Peak MCPA serum concentrations were 161 µg/ml and 259 µg/ml and peak bromoxynil concentrations were 119 µg/ml and 155 µg/ml in case 1 and 2, respectively. The estimated clearance of both herbicides by CVVHDF was low (<10 mL/min). CONCLUSION: CVVHDF did not result in significant clearance of either herbicide but may have assisted with hyperthermia control. Both patients survived with vigorous cooling, paralysis and ventilatory support.

Poisoning suicide with ingestion of the pyrethroids alpha-cypermethrin and deltamethrin and the antidepressant mirtazapine: A case report.

This case report describes a death attributed to the intake of the pyrethroid insecticides, alpha-cypermethrin and deltamethrin, and the antidepressant mirtazapine. The autopsy findings showed absence of external traumatic injuries and internal generalized visceral congestion, edema and cyanosis. The toxicological results revealed the presence of a toxic concentration of mirtazapine (12.5mg/L and 10.7mg/L in blood and urine, respectively) and high concentrations of pyrethroids (2.46mg/L alpha-cypermethrin and 2.40mg/L deltamethrin in blood, and 0.41mg/L alpha-cypermethrin and 0.46mg/L deltamethrin in urine, respectively). Blood ethanol concentration was 0.75g/L. All the evidence - from autopsy, police investigation and toxicology - was consistent with the intentional self-harm of the deceased. The current case was determined and recorded as a poisoning suicide. Cause of death of the deceased was reported as the synergistic toxicity of the ingested pyrethroids and mirtazapine. The presence of a significant blood ethanol concentration was considered a secondary contributory factor to the fatal outcome. The case presented herein is the first death attributed to poisoning from ingestion of pyrethroids in combination with mirtazapine, with the intention of the victim to cause self-harm, with corresponding toxicology results.

Worker illness related to ground application of pesticide--Kern County, California, 2005.

In California, suspected pesticide and work-related illnesses and injuries are reportable conditions. The Occupational Health Branch (OHB) of the California Department of Health Services (CDHS) conducts surveillance of work-related pesticide illness with support from the National Institute for Occupational Safety and Health (NIOSH) and the U.S. Environmental Protection Agency (EPA). On May 12, 2005, CDHS received a report from the California Department of Pesticide Regulation (CDPR) of a suspected pesticide incident in Kern County involving 27 farmworkers (age range: 21-61 years; median: 32.5 years) and six emergency responders (age range: 28-51 years; median: 33.5 years). CDHS investigated this incident by conducting a site visit; reviewing medical and meteorologic records; and interviewing affected workers, pesticide applicators, and the farmworker employer. Findings indicated that workers became ill from drift of a pyrethroid pesticide (cyfluthrin) that was being applied in a neighboring field. Pyrethroid pesticide applicators should always operate in a manner that ensures workers are not exposed.

A mixture of organophosphate and pyrethroid intoxication requiring intensive care unit admission: a diagnostic dilemma and therapeutic approach.

The illegal mixing of organophosphates and pyrethroids in marketed agriculture insecticides is becoming prevalent in developing countries. Over a 12-mo period, 8 patients were admitted to the emergency department of a university hospital in Dharan, Nepal after ingestion of such a mixture with suicidal intent. All patients presented with a combination of miosis, bradycardia, tachypnea, and unconsciousness. The occurrence of both pupillary dilation after a small-dose infusion of atropine (0.08 to 0.2 mg/kg in 1-3 h) and seizures raised the possibility of pyrethroid poisoning. In each case, an examination of the insecticide container confirmed that it contained a mixture of organophosphate and pyrethroid. After seizure control, gastric lavage, respiratory support, hemodynamic stabilization and diuresis, seven of the patients recovered without neurological deficit. One patient suffered aspiration pneumonia and died. The early clinical picture after this mixed poisoning is based on the toxicity of organophosphates rather than pyrethroids. Because the patients responded to a small dose of atropine with mydriasis and tachycardia, it suggested a mixed poisoning. Early suspicion of mixed poisoning may have a significant prognostic impact.

Two Fatal Intoxications with Cyanohydrins.

Cyanohydrins, also be called cyanoalcohols, are important industrial precursors to carboxylic acids and some amino acids. Acetone cyanohydrin (ACH) and formaldehyde cyanohydrin (glycolonitrile, FCH), which are the typical examples of cyanohydrins, are classified as extremely hazardous substances. As the cyanohydrins can readily decompose, and it is hard to find cyanohydrins in gastric contents and heart blood, the determination study in biological samples can be divided into two parts: the first is the determination of HCN by using a Prussian blue reaction and the HS-GC-MSD after derivatization by chloramine-T. The second is the determination of acetone or formaldehyde. In this part, headspace gas chromatography with flame ionization detector (HS-GC-FID) and solid phase microextraction (SPME)-gas chromatography with mass spectrometric detectors (GC-MSD) had been used. In this report, we reported two fatal intoxication cases of ACH and FCH; one person was killed by his wife by poisoning his food and the other was suicide by poison. Two real cases of ACH and FCH in human blood and gastric contents have been analyzed by using the above-mentioned method. The Prussian blue reaction was positive in the two cases. The peaks of acetone with retention times of 0.998 min appear in specimens of the deceased are consistent with the retention times of pure acetone. The peaks of formaldehyde with a retention time of 1.658 min appear in heart blood of the deceased, and the retention time of formaldehyde of the liquid is 1.674 min, which are consistent with the retention times of pure formaldehyde (1.673 min).

[Stevens-Johnson syndrome and toxic epidermal necrolysis (SJSTEN) related to insecticide: Second case in the literature and potential implications]. / Le syndrome de Stevens-Johnson-toxic epidermal necrolysis (SJSTEN) lié à un insecticide : second cas dans la littérature et implications potentielles.

INTRODUCTION: Stevens-Johnson syndrome and toxic epidermal necrolysis (SJSTEN) is a rare acute drug reaction characterized by the brutal destruction of the superficial layer of the skin and mucosa. SJSTEN is favoured by some drugs (90 % of cases) and genetic factors. It occurs at any age in both sexes. The pathophysiology is not completely understood. To our knowledge, only one case linked to an insecticide has been described. We present the second case involving a combination of lambdacyhalothrin and thiamethoxam. OBSERVATION: A 34-year-old farmer was admitted in emergency for a severe allergic reaction occurring few days after the use of an insecticide to treat his field with no particular precaution. The disease progression was swift: deterioration of general condition, generalized itching, blisters, bubbles, hyperthermia, tachycardia, significant oral pain and oral lesions and dysphagia. Hands, feet were concerned and external genitalia was responsible for burning urination. Oral lesions have rapidly evolved from edema to infected lesions. The diagnosis of SJSTEN was confirmed by histopathology. After complete assessment and adequate treatment, the patient was discharged after 17 days of hospitalization. The etiological research concluded to a probable poisoning by lambdacyhalothrin and thiamethoxam. DISCUSSION: This is the second published case of a SJSTEN linked to an insecticide combining lambdacyhalothrin and thiamethoxam. Manufacturers, users, regulators and physicians should take these data into account.

2-Methyl-4-chlorophenoxyacetic acid and bromoxynil herbicide death.

CASE REPORT: We report a fatal case of a 37 year old gentleman who ingested a MCPA/bromoxynil co-formulation herbicide. Although clinically well on initial examination, our patient declined dramatically over his 18 h admission with increasing CO2 production, hyperthermia and metabolic derangement to eventually die from cardiac asystole 20 h post ingestion. Two hours after ingestion the MCPA concentration was 83.9 µg/mL and bromoxynil concentration was 137 µg/mL. DISCUSSION: The patients' mechanism of death appeared to be uncoupling of oxidative phosphorylation, excess CO2 production and hyperthermia. There is limited knowledge on the acute toxicity of these herbicides, in particular bromoxynil, and this case highlights the relentless progression of severe toxicity in humans.

Subacute poisoning of mice with deltamethrin produces memory impairment, reduced locomotor activity, liver damage and changes in blood morphology in the mechanism of oxidative stress.

BACKGROUND: Deltamethrin (DEL) is a synthetic pyrethroid (PYR) insecticide, potent neurotoxicant. The current investigation was envisaged to explore behavioral, biochemical and morphologic effects of subacute poisoning with DEL in mice and to find one common mechanism of these changes. METHODS: Mice were daily injected ip with different doses of DEL: 8.3, 20.75 or 41.5mg/kg bw for 28 days. Their memory retention in passive avoidance task (PA), fresh spatial memory in a Y-maze and locomotor activity were measured once weekly. On day 29, blood morphology, alanine transaminase (ALT) activity and creatinine concentration in the blood sera, superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities were measured in the livers and kidneys. Livers were examined with light microscopy. RESULTS: Significant impairment of memory retention was recorded on day 2, 7 and 28 after exposure to DEL. Fresh spatial memory was significantly impaired by the highest dose of DEL on day 1, 14 and 28. Locomotor activity was reduced at every stage of experiment in all the groups exposed to DEL. In the animals exposed to the highest dose of DEL activities of alanine transaminase (ALT) and SOD were elevated, GPx was reduced, lymphocyte infiltrates were detected in the livers and there were changes in blood morphology. CONCLUSION: The results obtained indicate that liver and bone marrow, apart from the central nervous system (CNS) are damaged in the course of subacute poisoning with DEL. The possible common mechanism of the damage is oxidative stress.

The axonal pathology in chronic IDPN intoxication.

Neurofilamentous axonal swellings occur in a number of degenerative and toxic disorders of the nervous system. In one of these, experimental intoxication with beta, beta'-iminodiproprionitrile (IDPN), accumulation of neurofilaments has been shown to result from a defect in slow axonal transport. The consequence of this functional abnormality is a series of changes in axonal morphology: Neurofilaments accumulate in the proximal axon; the proximal axon becomes swollen; the distal axon loses volume (axonal atrophy). These studies indicate that axonal atrophy occurs secondary to an impairment of slow axonal transport and suggest that a similar abnormality may underlie the pathological changes in certain other degenerative and toxic diseases of the nervous system.

Studies on the etiology and pathogenesis of motor neuron diseases. II. Clinical and electrophysiologic features of pyramidal dysfunction in macaques fed Lathyrus sativus and IDPN.

A primate model of lathyrism has been produced in well-nourished male cynomolgus monkeys chronically fed a fortified diet composed of Lathyrus sativus (chickling or grass pea) and given daily per os an alcoholic extract of this legume. Animals given a diet of non-neurotoxic Cicer arietinum (chick pea) cross-matched with the nutritional properties of the experimental diet served as controls. Another group of animals received the same diet and oral doses of beta, beta'-iminodipropionitrile (IDPN), a reference compound that has been termed an "experimental neurolathyrogen." Monkeys fed Lathyrus developed clinical and electrophysiologic evidence of corticospinal deficits after 3 to 10 months of feeding. Animals administered IDPN showed clinical and/or electrophysiologic changes in the PNS and CNS motor and sensory pathways, and signs of cerebellar dysfunction. Since the two primate disorders are separable on clinical and electrophysiologic grounds, further use of the term "experimental neurolathyrogen" to describe the neurotoxic properties of IDPN seems inappropriate. These findings demonstrate the feasibility of developing a model of early human lathyrism in adequately nourished nonhuman primates.