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PubMed2004

Epidemiologic evidence for assessing the carcinogenicity of acrylamide.

Acrylamide (ACM) has recently been found in fried and baked foods, suggesting widespread public exposure. ACM is an industrial chemical that causes neurotoxicity in humans and an increase in benign tumors of the endocrine system of laboratory rats. The U.S. EPA and the International Agency for Research on Cancer (IARC) have designated ACM as a probable human carcinogen based on the bioassay data and evidence for a DNA reactive mechanism. We report here an assessment of the published epidemiological data with regard to exposure to ACM. The results of an epidemiology mortality study of heavily exposed workers published in 1999 failed to reveal any increase in total cancer in this workforce. The average total exposure in the exposed group was equivalent to over 100% of the estimated average lifetime dietary intake, assuming a U.S. diet. However, this epidemiologic information had limited power to detect modest increases in specific tumors of the type reported in the rodent studies. Although the mortality study could not have picked up the small increases in cancer or in specific cancer types predicted by EPA's linear extrapolation model, research on biochemical and physiological mechanisms suggests that EPA's assessment overstates the potency, and therefore, the risk from foods and other sources of exposure may be lower than previously anticipated.

Acrylamide↗
PubMed2001

Acrylamide-based monoliths as robust stationary phases for capillary electrochromatography.

A method is described for the synthesis of rigid, macroporous polymers (monoliths) to be used as stationary phases in capillary electrochromatography (CEC). The procedure reproducibly results in columns with good mechanical and chemical stability. Once the procedure was optimized, it yielded the desired CEC columns in nearly 100% of the cases. The batch-to-batch standard deviation of the migration of the electroosmotic flow (EOF) marker for nine randomly chosen columns was 5%. The polymerization is carried out inside the capillary, an aqueous phase is used as solvent. Monomers based on acrylamides with varying hydrophilicity were used to introduce the interactive moieties together with piperazine diacrylamide as cross-linker and vinylsulfonic acid as provider of the charged, EOF-producing moieties. The pore size of the monoliths was adjusted by adding varying amounts of ammonium sulfate to the reaction mixture. In this manner, the average pore size of a given monolith could be reproducibly adjusted to values ranging from 50 nm to 1.3 microm. The procedure was optimized for four particular types of monoliths, which differed in hydrophobicity. The latter was adjusted by introducing suitable co-monomers, such as alkyl chain-bearing molecules, into the monolithic structure. Attempts to systematically investigate the chromatographic behavior of the monolithic stationary phases were made, using a model mixture of aromatic compounds as sample. The standard deviations for the run-to-run reproducibility of the retention times for unretained and retained analytes were <1.5%. Flat Van Deemter curves were measured even at elevated flow-rates (2 mm/s). Plate heights between 10 and 15 microm were measured in this range. The retention order was taken as the principal indication for the chromatographic mode. The separation was found to be governed neither by pure reversed-phase nor by pure normal-phase chromatography, even on monoliths, where large amounts of C6 ligands had been introduced.

Acrylamides↗
PubMed2003

Acrylamide axonopathy revisited.

Distal swelling and eventual degeneration of axons in the CNS and PNS have been considered to be the characteristic neuropathological features of acrylamide (ACR) neuropathy. These axonopathic changes have been the basis for classifying ACR neuropathy as a central-peripheral distal axonopathy and, accordingly, research over the past 30 years has focused on the primacy of axon damage and on deciphering underlying mechanisms. However, based on accumulating evidence, we have hypothesized that nerve terminals, and not axons, are the primary site of ACR action and that compromise of corresponding function is responsible for the autonomic, sensory, and motor defects that accompany ACR intoxication (NeuroToxicology 23 (2002) 43). In this paper, we provide a review of data from a recently completed comprehensive, longitudinal silver stain study of brain and spinal cord from rats intoxicated with ACR at two different daily dosing rates, i.e., 50 mg/kg/day, ip or 21 mg/kg/day, po. Results show that, regardless of dose-rate, ACR intoxication was associated with early, progressive nerve terminal degeneration in all CNS regions and with Purkinje cell injury in cerebellum. At the lower dose-rate, initial nerve terminal argyrophilia was followed by abundant retrograde axon degeneration in white matter tracts of spinal cord, brain stem, and cerebellum. The results support and extend our nerve terminal hypothesis and suggest that Purkinje cell damage also plays a role in ACR neurotoxicity. Substantial evidence now indicates that axon degeneration is a secondary effect and is, therefore, not pathophysiologically significant. These findings have important implications for future mechanistic research, classification schemes, and assessment of neurotoxicity risk.

Acrylamide↗
PubMed2001

Metabolism, toxicokinetics and hemoglobin adduct formation in rats following subacute and subchronic acrylamide dosing.

Long-term, low-dose (subchronic) oral acrylamide (ACR) exposure produces peripheral nerve axon degeneration, whereas irreversible axon injury is not a component of short-term, higher dose (subacute) i.p. intoxication [Toxicol Appl Pharmacol 1998;151:211]. It is possible that this differential axonopathic expression is a product of exposure-dependent differences in ACR biotransformation and/or tissue distribution. Therefore, we determined the toxicokinetics and metabolism of ACR following subchronic oral (2.8 mM in drinking water for 34 days) or subacute i.p. (50 mg/kg per day for 11 days) administration to rats. Both dosing regimens produced moderate levels of behavioral neurotoxicity and, for each, ACR was rapidly absorbed from the site of administration and evenly distributed to tissues. Peak ACR plasma concentrations and tissue levels were directly related to corresponding daily dosing rates (20 or 50 mg/kg per day). During subchronic oral dosing a larger proportion (30%) of plasma ACR was converted to the epoxide metabolite glycidamide (GLY) than was observed following subacute i.p. intoxication (8%). This subchronic effect was not specifically related to changes in enzyme activities involved in GLY formation (cytochrome P450 2E1) ormetabolism (epoxide hydrolases). Both ACR and GLY formed hemoglobin adducts during subacute and subchronic dosing, the absolute quantity of which did not change as a function of neurotoxicant exposure. Compared to subacute i.p. exposure, the subchronic schedule produced approximately 30% less ACR adducts but two-fold more GLY adducts. GLY has been considered to be an active ACR metabolite and might mediate axon degeneration during subchronic ACR administration. However, corresponding peak GLY plasma concentrations were relatively low and previous studies have shown that GLY is only a weak neurotoxicant. Our study did not reveal other toxicokinetic idiosyncrasies that might be a basis for subchronic induction of irreversible axon damage. Consequently the mechanism of axon degeneration does not appear to involve route- or rate-dependent differences in metabolism or disposition.

Acrylamide↗
PubMed2002

Nerve terminals as the primary site of acrylamide action: a hypothesis.

Acrylamide (ACR) is considered to be prototypical among chemicals that cause a central-peripheral distal axonopathy. Multifocal neurofilamentous swellings and eventual degeneration of distal axon regions in the CNS and PNS have been traditionally considered the hallmark morphological features of this axonopathy. However, ACR has also been shown to produce early nerve terminal degeneration of somatosensory, somatomotor and autonomic nerve fibers under a variety of dosing conditions. Recent research from our laboratory has demonstrated that terminal degeneration precedes axonopathy during low-dose subchronic induction of neurotoxicity and occurs in the absence of axonopathy during higher-dose subacute intoxication. This relationship suggests that nerve terminal degeneration, and not axonopathy, is the primary or most important pathophysiologic lesion produced by ACR. In this hypothesis paper, we review evidence suggesting that nerve terminal degeneration is the hallmark lesion of ACR neurotoxicity, and we propose that this effect is mediated by the direct actions of ACR at nerve terminal sites. ACR is an electrophile and, therefore, sulfhydryl groups on presynaptic proteins represent rational molecular targets. Several presynaptic thiol-containing proteins (e.g. SNAP-25, NSF) are critically involved in formation of SNARE (soluble N-ethylmaleimide (NEM)-sensitive fusion protein receptor) complexes that mediate membrane fusion processes such as exocytosis and turnover of plasmalemmal proteins and other constituents. We hypothesize that ACR adduction of SNARE proteins disrupts assembly of fusion core complexes and thereby interferes with neurotransmission and presynaptic membrane turnover. General retardation of membrane turnover and accumulation of unincorporated materials could result in nerve terminal swelling and degeneration. A similar mechanism involving the long-term consequences of defective SNARE-based turnover of Na+/K(+)-ATPase and other axolemmal constituents might explain subchronic induction of axon degeneration. The ACR literature occupies a prominent position in neurotoxicology and has significantly influenced development of mechanistic hypotheses and classification schemes for neurotoxicants. Our proposal suggests a reevaluation of current classification schemes and mechanistic hypotheses that regard ACR axonopathy as a primary lesion.

Acrylamide↗
PubMed2002

Neurological evaluation of toxic axonopathies in rats: acrylamide and 2,5-hexanedione.

This research was conducted to determine which neurological test or combination of tests can provide sufficient functional information to compliment biochemical or morphological endpoints in mechanistic studies of toxic axonopathies. Using several neurological indices, we evaluated the effects of two prototypical neurotoxicants that cause distal axonopathy: acrylamide monomer (ACR) and 2,5-hexanedione (HD). For each toxicant, rats were exposed to two daily dosing rates (ACR, 50 mg/kg per day i.p. or 21 mg/kg per day, p.o.; HD, 175 or 400 mg/kg per day, p.o.) and neurological endpoints were determined two to three times per week. Specific tests included observations of spontaneous locomotion in an open field, and measurements of hindlimb landingfoot splay, forelimb and hindlimb grip strength and the hindlimb extensor thrust response. For all neurological parameters, the magnitude of defect induced by either neurotoxicant was not related to daily dose-rate, e.g. both the lower and higher ACR dose-rates produced the same degree of neurological dysfunction. Instead, dose-rate determined onset and progression of neurotoxicity, e.g. the higher ACR dose-rate produced moderate neurotoxicity after approximately 8 days of intoxication, whereas the lower dose-rate caused moderate neurotoxicity after 26 days. Regardless of dose-rate, ACR-exposed rats exhibited gait abnormalities (ataxia, splayed hindlimbs), in conjunction with increased landing hindfoot spread and decreased hindlimb grip strength and extensor thrust HD intoxicated rats exhibited hindlimb muscle weakness as indicated by a gait abnormality (dropped hocks) and decreases in grip strength and the extensor thrust response. However, hindlimb landingfoot spread was not affected by HD exposure. For both neurotoxicants, gait changes preceded or coincided with alterations in other neurologic indices. These results suggest that observations of spontaneous behavior in an open field represent a practical approach to assessing temporal development and extent of neurological dysfunction induced by axonopathic toxicants such as ACR and HD.

Acrylamide↗
PubMed2002

Fast axonal transport: a site of acrylamide neurotoxicity?

The cellular and molecular site and mode of action of acrylamide (ACR) leading to neurotoxicity has been investigated for four decades, without resolution. Although fast axonal transport compromise has been the central theme for several hypotheses, the results of many studies appear contradictory. Our analysis of the literature suggests that differing experimental designs and parameters of measurement are responsible for these discrepancies. Further investigation has demonstrated consistent inhibition of the quantity of bi-directional fast transport following single ACR exposures. Repeated compromise in fast anterograde transport occurs with each exposure. Modification of neurofilaments, microtubules, energy-generating metabolic enzymes and motor proteins are evaluated as potential sites of action causing the changes in fast transport. Supportive and contradictory data to the hypothesis that deficient delivery of fast-transported proteins to the axon causes, or contributes to, neurotoxicity are critically summarized. A hypothesis of ACR action is presented as a framework for future investigations.

Acrylamide↗
PubMed2002

Acrylamide neuropathy. II. Spatiotemporal characteristics of nerve cell damage in brainstem and spinal cord.

Previous studies of acrylamide (ACR) neuropathy in rat PNS [Toxicol. Appl. Pharmacol. 151 (1998) 211] and cerebellum [Neurotoxicology, 2002a] have suggested that axon degeneration was not a primary effect and was, therefore, of unclear neurotoxicological significance. To continue morphological examination of ACR neurotoxicity in CNS, a cupric silver stain method was used to define spatiotemporal characteristics of nerve cell body, dendrite, axon and terminal degeneration in brainstem and spinal cord. Rats were exposed to ACR at a dose-rate of either 50 mg/kg per day (i.p.) or 21 mg/kg per day (p.o.), and at selected times brains and spinal cord were removed and processed for silver staining. Results show that intoxication at the higher ACR dose-rate produced a nearly pure terminalopathy in brainstem and spinal cord regions, ie. widespread nerve terminal degeneration and swelling were present in the absence of significant argyrophilic changes in neuronal cell bodies, dendrites or axons. Exposure to the lower ACR dose-rate caused initial nerve terminal argyrophilia in selected brainstem and spinal cord regions. As intoxication continued, axon degeneration developed in white matter of these CNS areas. At both dose-rates, argyrophilic changes in brainstem nerve terminals developed prior to the onset of significant gait abnormalities. In contrast, during exposure to the lower ACR dose-rate the appearance of axon degeneration in either brainstem or spinal cord was relatively delayed with respect to changes in gait. Thus, regardless of dose-rate, ACR intoxication produced early, progressive nerve terminal degeneration. Axon degeneration occurred primarily during exposure to the lower ACR dose-rate and developed after the appearance of terminal degeneration and neurotoxicity. Spatiotemporal analysis suggested that degeneration began at the nerve terminal and then moved as a function of time in a somal direction along the corresponding axon. These data suggest that nerve terminals are a primary site of ACR action and that expression of axonopathy is restricted to subchronic dosing-rates.

Acrylamide↗
PubMed2002

Acrylamide neuropathy. I. Spatiotemporal characteristics of nerve cell damage in rat cerebellum.

Based on evidence from morphometric studies of PNS, we suggested that acrylamide (ACR)-induced distal axon degeneration was a secondary effect related to duration of exposure [Toxicol. Appl. Pharmacol. 151 (1998) 211]. To test this hypothesis in CNS, the cupric-silver stain method of de Olmos was used to define spatiotemporal characteristics of nerve somal, dendritic, axonal and terminal degeneration in rat cerebellum. Rats were exposed to ACR at either 50 mg/kg per day (i.p.) or 21 mg/kg per day (p.o.) and at selected times (i.p. = 5, 8 and 11 days; p.o. = 7, 14, 21, 28 and 38 days) brains were removed and processed for silver staining. Results demonstrate that intoxication at the higher ACR dose-rate produced early (day 5) and progressive degeneration of Purkinje cell dendrites in cerebellar cortex. Nerve terminal degeneration occurred concurrently with somatodendritic argyrophilia in cerebellar and brainstem nuclei that receive afferent input from Purkinje neurons. Relatively delayed (day 8), abundant axon degeneration was present in cerebellar white matter but not in cortical layers or in tracts carrying afferent fibers (cerebellar peduncles) from other brain nuclei. Axon argyrophilia coincided with the appearance of perikaryal degeneration, which was selective for Purkinje cells since silver impregnation of other cerebellar neurons was not evident in the different cortical layers or cerebellar nuclei. Intoxication at the lower ACR dose-rate produced simultaneous (day 14) dendrite, axon and nerve terminal argyrophilia and no somatic Purkinje cell degeneration. The spatiotemporal pattern of dendrite, axon and nerve terminal loss induced by both ACR dose-rates is consistent with Purkinje cell injury. Injured neurons are likely to be incapable of maintaining distal processes and, therefore, axon degeneration in the cerebellum is a component of a "dying-back" process of neuronal injury. Because cerebellar coordination of somatomotor activity is mediated solely through efferent projections of the Purkinje cell, injury to this neuron might contribute significantly to gait abnormalities that characterize ACR neurotoxicity.

Acrylamide↗
PubMed2003

Acrylamide neuropathy. III. Spatiotemporal characteristics of nerve cell damage in forebrain.

Previous studies of acrylamide (ACR) neuropathy in rat PNS [Toxicol. Appl. Pharmacol. (1998) 151:211-221] and in spinal cord, brainstem and cerebellum [NeuroToxicology (2002a) 23:397-414; NeuroToxicology (2002b) 23:415-429] have suggested that axon degeneration was not a primary effect and was, therefore, of unclear neurotoxicological significance. To conclude our studies of neurodegeneration in rat CNS during ACR neurotoxicity, a cupric silver stain method was used to define spatiotemporal characteristics of nerve cell body, dendrite, axon and terminal argyrophilia in forebrain regions and nuclei. Rats were exposed to ACR at a dose-rate of either 50 mg/kg per day (i.p.) or 21 mg/kg per day (p.o.) and at selected times brains were removed and processed for silver staining. Results show that intoxication at either ACR dose-rate produced a terminalopathy, i.e. nerve terminal degeneration and swelling were present in the absence of significant argyrophilic changes in neuronal cell bodies, dendrites or axons. Exposure to the higher ACR dose-rate caused early onset (day 5), widespread nerve terminal degeneration in most of the major forebrain areas, e.g. cerebral cortex, thalamus, hypothalamus and basal ganglia. At the lower dose-rate, nerve terminal degeneration in the forebrain developed early (day 7) but exhibited a relatively limited spatial distribution, i.e. anteroventral thalamic nucleus and the pars reticulata of the substantia nigra. Several hippocampal regions were affected at a later time point (day 28), i.e. CA1 field and subicular complex. At both dose-rates, argyrophilic changes in forebrain nerve terminals developed prior to the onset of significant gait abnormalities. Thus, in forebrain, ACR intoxication produced a pure terminalopathy that developed prior to the onset of significant neurological changes and progressed as a function of exposure. Neither dose-rate used in this study was associated with axon degeneration in any forebrain region. Our findings indicate that nerve terminals were selectively affected in forebrain areas and, therefore, might be primary sites of ACR action.

Acrylamide↗
PubMed2003

Acrylamide neuropathy. II. Spatiotemporal characteristics of nerve cell damage in brainstem and spinal cord.

Previous studies of acrylamide (ACR) neuropathy in rat PNS [Toxicol. Appl. Pharmacol. 151 (1998) 211] and cerebellum [NeuroToxicology 23 (2002) 397] have suggested that axon degeneration was not a primary effect and was, therefore, of unclear neurotoxicological significance. To continue morphological examination of ACR neurotoxicity in CNS, a cupric silver stain method was used to define spatiotemporal characteristics of nerve cell body, dendrite, axon and terminal degeneration in brainstem and spinal cord. Rats were exposed to ACR at a dose-rate of either 50 mg/kg per day (i.p.) or 21 mg/kg per day (p.o.), and at selected times brains and spinal cord were removed and processed for silver staining. Results show that intoxication at the higher ACR dose-rate produced a nearly pure terminalopathy in brainstem and spinal cord regions, i.e. widespread nerve terminal degeneration and swelling were present in the absence of significant argyrophilic changes in neuronal cell bodies, dendrites or axons. Exposure to the lower ACR dose-rate caused initial nerve terminal argyrophilia in selected brainstem and spinal cord regions. As intoxication continued, axon degeneration developed in white matter of these CNS areas. At both dose-rates, argyrophilic changes in brainstem nerve terminals developed prior to the onset of significant gait abnormalities. In contrast, during exposure to the lower ACR dose-rate the appearance of axon degeneration in either brainstem or spinal cord was relatively delayed with respect to changes in gait. Thus, regardless of dose-rate, ACR intoxication produced early, progressive nerve terminal degeneration. Axon degeneration occurred primarily during exposure to the lower ACR dose-rate and developed after the appearance of terminal degeneration and neurotoxicity. Spatiotemporal analysis suggested that degeneration began at the nerve terminal and then moved as a function of time in a somal direction along the corresponding axon. These data suggest that nerve terminals are a primary site of ACR action and that expression of axonopathy is restricted to subchronic dosing-rates.

Acrylamide↗
PubMed2004

In vivo and in vitro effects of acrylamide on synaptosomal neurotransmitter uptake and release.

Evidence suggests acrylamide (ACR) neurotoxicity is mediated by impaired presynaptic transmission. To assess the effects of ACR on nerve terminal function, [3H] glutamate release and uptake were determined in brain synaptosomes isolated from intoxicated rats (50mg/kg per day x 8 days, i.p. or 21 mg/kg per day x 21 days, p.o.). Regardless of ACR dose-rate, a significant reduction in synaptosomal K(+)-stimulated, Ca(2+)-dependent release was detected, whereas kinetic analysis of Na(+)-dependent uptake did not reveal consistent changes. Immunoblot analysis showed normal protein levels (e.g. SNAP-25) in dysfunctional synaptosomes isolated from ACR-intoxicated rats. This suggests that defective release does not involve changes in protein synthesis and/or anterograde delivery of presynaptic constituents. To identify potential targets, synaptosomes were exposed in vitro to [ 14C ]-ACR and radiolabeled proteins were separated by gel electrophoresis and detected by autoradiography. [14C]-ACR labeling of distinct synaptosomal protein bands (10.5-154000 kDa) was blocked by the sulfhydryl alkylating agent, N-ethylmaleimide (NEM; 4mM) but not by the non-neurotoxic structural analog propionamide (10mM). In vitro characterization of synaptosomal [3H] glutamate uptake and release showed that ACR, NEM and iodoacetic acid (IAA) produced concentration-dependent decreases in each parameter that were highly correlated to reductions in free sulfhydryl content. All three chemicals were equiefficacious with respect to reducing sulfhydryl content and neurotransmitter uptake/release, although the relative potencies differed; [3H]. Kinetic analysis of uptake showed that in vitro exposure to ACR, IAA or NEM at their respective IC(50)'s caused similar reductions in V(max). These data suggest that ACR-induced synaptic dysfunction involves adduction of presynaptic protein thiol groups and subsequent reduction in neurotransmitter release.

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PubMed2002

Hemoglobin adducts of ethylene oxide, propylene oxide, acrylonitrile and acrylamide-biomarkers in occupational and environmental medicine.

In a chemical plant, ethylene oxide (EO) and propylene oxide (PO) were used for the production of surfactants for the textile industry. Within health supervision, we investigated the internal exposure of the workers using hemoglobin adducts as parameters of biochemical effects. The 95th percentile for N-2-hydroxyethylvaline (HEV) was 1280 pmol/g globin (=29.4 microg/l blood) in blood from exposed workers compared with 100 pmol/g globin (or 2.3 microg/l) in controls. N-(R,S)-2-hydroxypropylvaline (HPV) both in workers and controls was below the detection limit (80 pmol/g globin or 2 microg/l). The levels of the adducts of acrylonitrile (ACN) and acrylamide (AA) were also determined, though they were mainly accounted for by smoking and diet. Median values of N-2-cyanoethylvaline (CEV) were below 4 pmol/g globin (or 0.1 microg/l) in non-smokers (n=24) and 131 pmol/g globin (or 3.3 microg/l) in smokers (n=38). Median values of N-2-carbamoylethylvaline (AAV) were 22 pmol/g globin (or 0.6 microg/l) in non-smokers compared with 89 pmol/g globin (or 2.4 microg/l) in smokers. Correlations were found between smoking habits and adduct levels of CEV and AAV.

Acrylamide↗
PubMed2001

Separation of DNA fragments and single strand conformation polymorphism analysis in bare capillaries using poly(acrylamide-dimethylacrylamide) as a separation medium.

A short chain poly(acrylamide-dimethylacrylamide) (PADMA) was synthesized in aqueous phase using isopropanol as a chain transfer agent, and was characterized according to the chemical composition and molecular mass. This polymer can form a stable dynamic coating on the inner surface of the capillary, thereby suppressing the electroosmotic flow and DNA-capillary wall interaction. The sieving medium has low viscosity and capillary filling with this medium and medium replacement were conveniently carried out by commercial capillary electrophoresis instruments. The effects of components and concentration of copolymers on the separation of DNA fragments were investigated. Highly efficient separation of DNA fragments, successful single strand conformation polymorphism (SSCP) analysis and good reproducibility of the migration time were obtained in bare capillaries using these copolymers as sieving media. Our preliminary results demonstrate that PADMA will become an alternative matrix for DNA separation by capillary electrophoresis.

Acrylamides↗
PubMed2003

Transdermal application of bupivacaine-loaded poly(acrylamide(A)-co-monomethyl itaconate) hydrogels.

Bupivacaine, an amide local anaesthetic agent of long-acting and intense anaesthesia, was incorporated into poly(acrylamide(A)-co-monomethyl itaconate (MMI)) hydrogels. The swelling behaviour of two gel compositions, without drug, 75A/25MMI and 60A/40MMI, through rabbit ear skin, mounted on a modified Franz diffusion cell, was studied. Both gel compositions reach the equilibrium swelling degree (88.9+/-0.7 wt.% for 75A/25MMI and 92.5+/-0.1 wt.% for 60A/40MMI). The swelling kinetics was in accordance with the second Fick's Law; diffusion coefficients indicate faster swelling for gels with lower amount of monomethyl itaconic acid. The skin flux of bupivacaine solution through rabbit ear skin was 105+/-24 microg/cm(2)/h, the effective permeability coefficient was 26 x 10(-3)+/-9 x 10(-3)cm/h, and 77+/-15% of bupivacaine was permeated. Bupivacaine-loaded gels allow the drug was permeated through the skin. 47+/-4% and 36+/-3% of the drug amount included in 75A/25MMI and 60A/40MMI hydrogels, respectively, was permeated. The skin flux of the drug was between 90+/-5 and 16+/-7 microg/cm(2)/h depending on the amount of bupivacaine included in the gel and the gel composition. Skin flux increases with the drug load of the gels. Furthermore, as more MMI in the gel slower skin flux of the drug due to bupivacaine-gel interactions.

Acrylamides↗
PubMedDate not supplied

Relationship between acrylamide reproductive and neurotoxicity in male rats.

To determine whether there is a relationship between the reproductive and neurotoxic effects of acrylamide monomer (AM), the first week of the study design of Sublet et al. ¿14 was duplicated: Long-Evans male rats were gavaged with AM in water, 25/group, at 0, 5, 15, 30, 45, or 60 mg/kg/day for 5 days (days 1 through 5). On Day 8, males were paired overnight with untreated virgin females (1 : 1) in proestrus/estrus. On day 9, males were evaluated for forelimb and hindlimb grip strength. Five males/group were perfusion fixed, 20/group were used for andrologic assessment, and all were necropsied. Perfusion-fixed sciatic nerves were examined histologically. Sperm-positive females were examined for preimplantation and postimplantation loss at midpregnancy. At 15 to 60 mg/kg/day, males exhibited significantly reduced weight gain, reduced mating, fertility, and pregnancy indices by trend analysis (significant at 60 mg/kg/d by pairwise comparison), and increased postimplantation loss and dominant lethal factor, F(L)%, at 45 and 60 mg/kg/day. At 60 mg/kg/day, the sperm beat cross frequency was increased, with no significant effects on epididymal sperm motility or concentration, and hindlimb grip strength was decreased, with no pathologic lesions in sciatic nerves. Therefore, epididymal sperm, mating, and neurotoxic effects were observed at AM doses that also resulted in increased postimplantation loss, possibly by different mechanisms.

Acrylamide↗
PubMedDate not supplied

Rat two-generation reproduction and dominant lethal study of acrylamide in drinking water.

Fischer 344 (F344) F(0) weanling rats, 30/sex/group, were exposed to acrylamide in drinking water at 0.0, 0.5, 2.0, or 5.0 mg/kg/day for 10 weeks and then mated. Exposure of F(0) females continued through gestation and lactation of F(1) litters. F(0) males, after F(0) mating, were removed from exposure and mated (one male: two untreated females) for the dominant lethal (DL) assay. Thirty F(l) weanlings/sex/group were exposed for 11 weeks to the same dose levels as their parents, and then mated to produce F(2) offspring. F(0) and F(l) parents and F(1) and F(2) weanlings were necropsied. Prebreeding exposure of F(0) and F(l) animals resulted in systemic toxicity at 2.0 to 5.0 mg/kg/day, with head tilt and/or foot splay increased at 0.5 to 5.0 mg/kg/day. F(0) and F(l) reproductive indices and gestational length were unaffected. Implantations and live pups/litter at birth were reduced at 5.0 mg/kg/day. Survival of F(l) and F(2) pups was reduced at 5.0 mg/kg/day for PND 0 through 4 only. In the DL assay, total and live implants were reduced, pre- and postimplantation loss was increased, and the frequency of DL factors (F(L)%) was increased at 5.0 mg/kg/day. At 5.0 mg/kg/day, adult F(l) male peripheral nerves exhibited axonal fragmentation and/or swelling; F(l) female spinal cord sections were unremarkable. The NOEL for prenatal DL was 2.0 mg/kg/day; the NOEL for adult systemic toxicity, including neurotoxicity, was < or = 0.5 mg/kg/day. Therefore, neurotoxicity and DL were differentially affected.

Acrylamide↗
PubMedDate not supplied

Effects of lactational administration of acrylamide on rat dams and offspring.

We duplicated the study design of Husain et al. (Ind Health 1987; 25:19-28) to determine whether maternal exposure to acrylamide monomer (AM) resulted in offspring neurotoxicity. Wistar rat dams with litters (15/group) were gavaged with AM in saline at 0 or 25.0 mg/kg/d throughout lactation (pnd 0-21). Maternal feed and water consumption, body weights (BW), and Functional Observational Battery (FOB) were recorded. At weaning (pnd 21), maternal sciatic nerves were examined histologically. Male offspring were retained until pnd 91, with BW and grip strength evaluations. Dosed dams exhibited progressive toxicity, including mortality (two), severely reduced feed and water consumption, BW, and BW gain, and behavioral neurotoxicity (with no sciatic nerve pathology). Nursing offspring at 25.0 mg/kg/d exhibited increased mortality and reduced BW associated with little/no milk in stomachs. Postwean males at 25.0 mg/kg/d exhibited normal BW gain and increasing grip strength over time. Therefore, AM caused maternal toxicity; offspring effects during lactation were consistent with inanition from maternal toxicity. Postwean males exhibited recovery with no signs of AM-mediated toxicity. These results do not support the conclusions of Husain et al.

Acrylamide↗