Neurotoxicity and mechanistic data were collected for six alpha-cyano pyrethroids (beta-cyfluthri... more Neurotoxicity and mechanistic data were collected for six alpha-cyano pyrethroids (beta-cyfluthrin, cypermethrin, deltamethrin, esfenvalerate, fenpropathrin and lambda-cyhalothrin) and up to six non-cyano containing pyrethroids (bifenthrin, S-bioallethrin [or allethrin], permethrin, pyrethrins, resmethrin [or its cis-isomer, cismethrin] and tefluthrin under standard conditions. Factor analysis and multivariate dissimilarity analysis were employed to evaluate four independent data sets comprised of (1) fifty-six behavioral and physiological parameters from an acute neurotoxicity functional observatory battery (FOB), (2) eight electrophysiological parameters from voltage clamp experiments conducted on the Na(v)1.8 sodium channel expressed in Xenopus oocytes, (3) indices of efficacy, potency and binding calculated for calcium ion influx across neuronal membranes, membrane depolarization and glutamate released from rat brain synaptosomes and (4) changes in chloride channel open state probability using a patch voltage clamp technique for membranes isolated from mouse neuroblastoma cells. The pyrethroids segregated into Type I (T--syndrome-tremors) and Type II (CS syndrome--choreoathetosis with salivation) groups based on FOB data. Of the alpha-cyano pyrethroids, deltamethrin, lambda-cyhalothrin, cyfluthrin and cypermethrin arrayed themselves strongly in a dose-dependent manner along two factors that characterize the CS syndrome. Esfenvalerate and fenpropathrin displayed weaker response profiles compared to the non-cyano pyrethroids. Visual clustering on multidimensional scaling (MDS) maps based upon sodium ion channel and calcium influx and glutamate release dissimilarities gave similar groupings. The non-cyano containing pyrethroids were arrayed in a dose-dependent manner along two different factors that characterize the T-syndrome. Bifenthrin was an outlier when MDS maps of the non-cyano pyrethroids were based on sodium ion channel characteristics and permethrin was an outlier when the MDS maps were based on calcium influx/glutamate release potency. Four of six alpha-cyano pyrethroids (lambda-cyfluthrin, cypermethrin, deltamethrin and fenpropathrin) reduced open chloride channel probability. The R-isomers of lambda-l-cyhalothrin reduced open channel probability whereas the S-isomers, antagonized the action of the R-isomers. None of the non-cyano pyrethroids reduced open channel probability, except bioallethrin, which gave a weak response. Overall, based upon neurotoxicity data and the effect of pyrethroids on sodium, calcium and chloride ion channels, it is proposed that bioallethrin, cismethrin, tefluthrin, bifenthrin and permethrin belong to one common mechanism group and deltamethrin, lambda-cyhalothrin, cyfluthrin and cypermethrin belong to a second. Fenpropathrin and esfenvalerate occupy an intermediate position between these two groups
Publisher Summary This chapter presents an assessment of the toxicity of avermectins. Abamectin b... more Publisher Summary This chapter presents an assessment of the toxicity of avermectins. Abamectin belongs to a general class of closely related macrocyclic lactones either produced directly by the actinomycete Streptomyces avermitilis or generated through semisynthetic modifications. They penetrate the leaves and break down rapidly in sunlight; all of these features favor their use in integrated pest management. Abamectin is used primarily to control mites, and emamectin benzoate is used to control lepidopterian species in vegetables, cotton, and tobacco. They act as chloride channel blockers, causing hyperexcitability and convulsions. Avermectin intoxication in mammals begins with hyperexcitability, tremors, and incoordination and later develops into ataxia and coma-like sedation. The avermectins increase membrane permeability to chloride ions and act as GABAA agonists; this is similar to the mode of action of the benzodiazepine sedatives. Their toxicity reflects this mode of action in overdose scenarios and in animal models with compromised P-glycoprotein barriers. They are not genotoxic, as has been demonstrated in a variety of standard tests for mutagenicity, clastogenicity, and unscheduled deoxyribonucleic acid (DNA) synthesis. Ivermectin has been used clinically for over a decade for the control of Onchocerca volvulus and other parasites in veterinary and human medicine. The assessment of the toxicity of the avermectins in the presence or absence of an intact placental–fetal barrier in rodents is an illustrative case study of the effect of species differences in the expression of efflux transporters. As long as animal models continue to be used to characterize potential risks to the human population, it will continue to be of critical importance to appreciate that the genetic differences underlying the manifestations of toxicity in animal models may not necessarily be appropriate for extrapolation of risk to man.
Journal of biochemical and molecular toxicology, 2014
Dear Editor, We read with interest the article, The Perplexing Paradox of Paraquat: The Case for ... more Dear Editor, We read with interest the article, The Perplexing Paradox of Paraquat: The Case for Host-Based Susceptibility and Postulated Neurodegenerative Effects Byron C. Jones, Xuemei Huang, Richard B. Mailman, Lu Lu, and Robert W. Williams, Journal of Biochemical and Molecular Toxicology 00:1–7, 2014, DOI 10.1002/jbt.21552, which suggests a number of technical and biological mechanisms that could contribute to inconsistencies in the published literature on the neurotoxicity of paraquat. We would like to comment on some of the points made in the article. In the section headed “Why the disparity,” we would like to highlight that the mice used in [2] were C57Bl/6 sourced from Jackson Laboratories, Bar Harbor, a strain and source previously demonstrated by others to be sensitive to the effects of MPTP. These animals were 9–10 weeks old at the start of dosing. However, in a subsequent 13-week dietary administration study, [3], in which we again found no effect of paraquat on dopaminergic neurons using the robust combination of neuropathology, stereology, and neurochemistry, the mice (of identical strain and source) were 10 weeks old at the start of the study and 23 weeks (5–6 months) old at termination. [4] reported no difference in the extent of dopaminergic cell loss (25%) between 6-weekand 5-month-old mice and only a slight but statistically significant (p < 0.05) increase in susceptibility in the oldest (18-month old) animals (33% reduction of TH-positive neurons). We do not therefore consider that the strain/source or age of the mice is necessarily one of the key variables capable of explaining discrepancies in the findings of different research groups. We would also like to clarify that paraquat is no longer used in the European Union (EU) following an EU Court of First Instance ruling against the European Commission for procedural reasons, resulting in the annulment of the EU Directive, which included paraquat in the list of EU approved substances. Importantly, the EU regulatory science review concluded that use of paraquat does not result in unacceptable risk to human health or to the environment.
Bradford Hill's viewpoints were used to conduct a weight-of-the-evidence assessment of the as... more Bradford Hill's viewpoints were used to conduct a weight-of-the-evidence assessment of the association between Parkinson's disease (PD) and rural living, farming and pesticide use. The results were compared with an assessment based upon meta-analysis. For comparison, we also evaluated the association between PD and cigarette smoking as a "positive control" because a strong inverse association has been described consistently in the literature. PubMed was searched systematically to identify all published epidemiological studies that evaluated associations between Parkinson's disease (PD) and cigarette smoking, rural living, well-water consumption, farming and the use of pesticides, herbicides, insecticides, fungicides or paraquat. Studies were categorized into two study quality groups (Tier 1 or Tier 2); data were abstracted and a forest plot of relative risks (RRs) was developed for each risk factor. In addition, when available, RRs were tabulated for more highl...
Atrazine suppression of the LH surge slowly develops over time and peaks after 4 days; sensitivit... more Atrazine suppression of the LH surge slowly develops over time and peaks after 4 days; sensitivity to atrazine decreases after 8 or 14 days of dosing. Adaptation of the LH response was correlated with increased phase I and phase II liver enzyme activity/expression. The effect of atrazine on the LH surge was evaluated in female Sprague-Dawley rats administered 100 mg/kg/day atrazine by gavage for 1, 2, 3, or 4 consecutive days or 6.5, 50, or 100 mg/kg/day atrazine for 4, 8, or 14 days. No statistically significant effects of atrazine were seen on peak plasma LH or LH area under the curve (AUC) after one, two, or three doses of 100 mg/kg/day. Four daily doses of 50 or 100 mg/kg atrazine significantly reduced peak LH and LH AUCs, whereas 6.5 mg/kg/day had no effect. After 8 or 14 days of treatment, statistically significantly reduced peak LH and LH AUC were observed in the 100 mg/kg/day dose group, but not in the 6.5 or 50 mg/kg/day dose groups, although significantly reduced LH was ob...
It is known that human subjects deprived of meaningful visual, auditory and somatosensory stimula... more It is known that human subjects deprived of meaningful visual, auditory and somatosensory stimulation (sensory deprivation), spend a larger portion of their time asleep (increased Stage I &amp; II) than when in a normal environment. Furthermore, that phase of sleep which is characterized by the presence of rapid eye movements (REM sleep) is altered under these conditions, with REM density
The neurotoxicity of paraquat dichloride (PQ) was assessed in two inbred strains of 9- or 16-week... more The neurotoxicity of paraquat dichloride (PQ) was assessed in two inbred strains of 9- or 16-week old male C57BL/6 mice housed in two different laboratories and compared to the effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). PQ was administered by intraperitoneal injections; either once (20 mg/kg) or twice (10 mg/kg) weekly for 3 weeks, while MPTP-HCl was injected 4 times on a single day (20 mg/kg/dose). Brains were collected 8, 16, 24, 48, 96 or 168 hours after the last PQ treatment, and 48 or 168 hours after MPTP treatment. Dopamine neurons in the substantia nigra pars compacta (SNpc) were identified by antibodies to tyrosine hydroxylase (TH+) and microglia were identified using Iba-1 immunoreactivity. The total number of TH+ neurons and the number of resting and activated microglia in the SNpc at 168 hours after the last dose were estimated using model- or design-based stereology, with investigators blinded to treatment. In a further analysis, a pathologist, also ...
Neurotoxicity and mechanistic data were collected for six alpha-cyano pyrethroids (beta-cyfluthri... more Neurotoxicity and mechanistic data were collected for six alpha-cyano pyrethroids (beta-cyfluthrin, cypermethrin, deltamethrin, esfenvalerate, fenpropathrin and lambda-cyhalothrin) and up to six non-cyano containing pyrethroids (bifenthrin, S-bioallethrin [or allethrin], permethrin, pyrethrins, resmethrin [or its cis-isomer, cismethrin] and tefluthrin under standard conditions. Factor analysis and multivariate dissimilarity analysis were employed to evaluate four independent data sets comprised of (1) fifty-six behavioral and physiological parameters from an acute neurotoxicity functional observatory battery (FOB), (2) eight electrophysiological parameters from voltage clamp experiments conducted on the Na(v)1.8 sodium channel expressed in Xenopus oocytes, (3) indices of efficacy, potency and binding calculated for calcium ion influx across neuronal membranes, membrane depolarization and glutamate released from rat brain synaptosomes and (4) changes in chloride channel open state probability using a patch voltage clamp technique for membranes isolated from mouse neuroblastoma cells. The pyrethroids segregated into Type I (T--syndrome-tremors) and Type II (CS syndrome--choreoathetosis with salivation) groups based on FOB data. Of the alpha-cyano pyrethroids, deltamethrin, lambda-cyhalothrin, cyfluthrin and cypermethrin arrayed themselves strongly in a dose-dependent manner along two factors that characterize the CS syndrome. Esfenvalerate and fenpropathrin displayed weaker response profiles compared to the non-cyano pyrethroids. Visual clustering on multidimensional scaling (MDS) maps based upon sodium ion channel and calcium influx and glutamate release dissimilarities gave similar groupings. The non-cyano containing pyrethroids were arrayed in a dose-dependent manner along two different factors that characterize the T-syndrome. Bifenthrin was an outlier when MDS maps of the non-cyano pyrethroids were based on sodium ion channel characteristics and permethrin was an outlier when the MDS maps were based on calcium influx/glutamate release potency. Four of six alpha-cyano pyrethroids (lambda-cyfluthrin, cypermethrin, deltamethrin and fenpropathrin) reduced open chloride channel probability. The R-isomers of lambda-l-cyhalothrin reduced open channel probability whereas the S-isomers, antagonized the action of the R-isomers. None of the non-cyano pyrethroids reduced open channel probability, except bioallethrin, which gave a weak response. Overall, based upon neurotoxicity data and the effect of pyrethroids on sodium, calcium and chloride ion channels, it is proposed that bioallethrin, cismethrin, tefluthrin, bifenthrin and permethrin belong to one common mechanism group and deltamethrin, lambda-cyhalothrin, cyfluthrin and cypermethrin belong to a second. Fenpropathrin and esfenvalerate occupy an intermediate position between these two groups
Publisher Summary This chapter presents an assessment of the toxicity of avermectins. Abamectin b... more Publisher Summary This chapter presents an assessment of the toxicity of avermectins. Abamectin belongs to a general class of closely related macrocyclic lactones either produced directly by the actinomycete Streptomyces avermitilis or generated through semisynthetic modifications. They penetrate the leaves and break down rapidly in sunlight; all of these features favor their use in integrated pest management. Abamectin is used primarily to control mites, and emamectin benzoate is used to control lepidopterian species in vegetables, cotton, and tobacco. They act as chloride channel blockers, causing hyperexcitability and convulsions. Avermectin intoxication in mammals begins with hyperexcitability, tremors, and incoordination and later develops into ataxia and coma-like sedation. The avermectins increase membrane permeability to chloride ions and act as GABAA agonists; this is similar to the mode of action of the benzodiazepine sedatives. Their toxicity reflects this mode of action in overdose scenarios and in animal models with compromised P-glycoprotein barriers. They are not genotoxic, as has been demonstrated in a variety of standard tests for mutagenicity, clastogenicity, and unscheduled deoxyribonucleic acid (DNA) synthesis. Ivermectin has been used clinically for over a decade for the control of Onchocerca volvulus and other parasites in veterinary and human medicine. The assessment of the toxicity of the avermectins in the presence or absence of an intact placental–fetal barrier in rodents is an illustrative case study of the effect of species differences in the expression of efflux transporters. As long as animal models continue to be used to characterize potential risks to the human population, it will continue to be of critical importance to appreciate that the genetic differences underlying the manifestations of toxicity in animal models may not necessarily be appropriate for extrapolation of risk to man.
Journal of biochemical and molecular toxicology, 2014
Dear Editor, We read with interest the article, The Perplexing Paradox of Paraquat: The Case for ... more Dear Editor, We read with interest the article, The Perplexing Paradox of Paraquat: The Case for Host-Based Susceptibility and Postulated Neurodegenerative Effects Byron C. Jones, Xuemei Huang, Richard B. Mailman, Lu Lu, and Robert W. Williams, Journal of Biochemical and Molecular Toxicology 00:1–7, 2014, DOI 10.1002/jbt.21552, which suggests a number of technical and biological mechanisms that could contribute to inconsistencies in the published literature on the neurotoxicity of paraquat. We would like to comment on some of the points made in the article. In the section headed “Why the disparity,” we would like to highlight that the mice used in [2] were C57Bl/6 sourced from Jackson Laboratories, Bar Harbor, a strain and source previously demonstrated by others to be sensitive to the effects of MPTP. These animals were 9–10 weeks old at the start of dosing. However, in a subsequent 13-week dietary administration study, [3], in which we again found no effect of paraquat on dopaminergic neurons using the robust combination of neuropathology, stereology, and neurochemistry, the mice (of identical strain and source) were 10 weeks old at the start of the study and 23 weeks (5–6 months) old at termination. [4] reported no difference in the extent of dopaminergic cell loss (25%) between 6-weekand 5-month-old mice and only a slight but statistically significant (p < 0.05) increase in susceptibility in the oldest (18-month old) animals (33% reduction of TH-positive neurons). We do not therefore consider that the strain/source or age of the mice is necessarily one of the key variables capable of explaining discrepancies in the findings of different research groups. We would also like to clarify that paraquat is no longer used in the European Union (EU) following an EU Court of First Instance ruling against the European Commission for procedural reasons, resulting in the annulment of the EU Directive, which included paraquat in the list of EU approved substances. Importantly, the EU regulatory science review concluded that use of paraquat does not result in unacceptable risk to human health or to the environment.
Bradford Hill's viewpoints were used to conduct a weight-of-the-evidence assessment of the as... more Bradford Hill's viewpoints were used to conduct a weight-of-the-evidence assessment of the association between Parkinson's disease (PD) and rural living, farming and pesticide use. The results were compared with an assessment based upon meta-analysis. For comparison, we also evaluated the association between PD and cigarette smoking as a "positive control" because a strong inverse association has been described consistently in the literature. PubMed was searched systematically to identify all published epidemiological studies that evaluated associations between Parkinson's disease (PD) and cigarette smoking, rural living, well-water consumption, farming and the use of pesticides, herbicides, insecticides, fungicides or paraquat. Studies were categorized into two study quality groups (Tier 1 or Tier 2); data were abstracted and a forest plot of relative risks (RRs) was developed for each risk factor. In addition, when available, RRs were tabulated for more highl...
Atrazine suppression of the LH surge slowly develops over time and peaks after 4 days; sensitivit... more Atrazine suppression of the LH surge slowly develops over time and peaks after 4 days; sensitivity to atrazine decreases after 8 or 14 days of dosing. Adaptation of the LH response was correlated with increased phase I and phase II liver enzyme activity/expression. The effect of atrazine on the LH surge was evaluated in female Sprague-Dawley rats administered 100 mg/kg/day atrazine by gavage for 1, 2, 3, or 4 consecutive days or 6.5, 50, or 100 mg/kg/day atrazine for 4, 8, or 14 days. No statistically significant effects of atrazine were seen on peak plasma LH or LH area under the curve (AUC) after one, two, or three doses of 100 mg/kg/day. Four daily doses of 50 or 100 mg/kg atrazine significantly reduced peak LH and LH AUCs, whereas 6.5 mg/kg/day had no effect. After 8 or 14 days of treatment, statistically significantly reduced peak LH and LH AUC were observed in the 100 mg/kg/day dose group, but not in the 6.5 or 50 mg/kg/day dose groups, although significantly reduced LH was ob...
It is known that human subjects deprived of meaningful visual, auditory and somatosensory stimula... more It is known that human subjects deprived of meaningful visual, auditory and somatosensory stimulation (sensory deprivation), spend a larger portion of their time asleep (increased Stage I &amp; II) than when in a normal environment. Furthermore, that phase of sleep which is characterized by the presence of rapid eye movements (REM sleep) is altered under these conditions, with REM density
The neurotoxicity of paraquat dichloride (PQ) was assessed in two inbred strains of 9- or 16-week... more The neurotoxicity of paraquat dichloride (PQ) was assessed in two inbred strains of 9- or 16-week old male C57BL/6 mice housed in two different laboratories and compared to the effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). PQ was administered by intraperitoneal injections; either once (20 mg/kg) or twice (10 mg/kg) weekly for 3 weeks, while MPTP-HCl was injected 4 times on a single day (20 mg/kg/dose). Brains were collected 8, 16, 24, 48, 96 or 168 hours after the last PQ treatment, and 48 or 168 hours after MPTP treatment. Dopamine neurons in the substantia nigra pars compacta (SNpc) were identified by antibodies to tyrosine hydroxylase (TH+) and microglia were identified using Iba-1 immunoreactivity. The total number of TH+ neurons and the number of resting and activated microglia in the SNpc at 168 hours after the last dose were estimated using model- or design-based stereology, with investigators blinded to treatment. In a further analysis, a pathologist, also ...
Uploads
Papers by Charles Breckenridge