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Comparison of benchmark doses (BMD) with no-observed-adverse-effect-levels (NOAELs) and low-observed-adverse-effect-levels (LOAELs) for subchronic toxicity studies
Book ofAhmucts - EUROTOX 94 rats at age of 12 weeks was registered with chronic electrodes impfantated on the primary somatosensory, visual and auditory centres. The analysed parameters of tha spontaneous EEG of the freely-moving rats were the mean amplitude. mean frequency, EEG index and the power spectrum of the frequency wave bands. These characteristics of the EEGs were also i-tigated after visual and acoustical stimulations of the rats. The data showed that all the compounds caused dose-dependent changes of the spontaneous EEG: increase of the rnaan frequency and EEG index. decrease of the mean amplitude, etc. There were no significant differences among the EEG changes caused by tfte isotoxic doses of the three compou~lds when the data of the identically treated rats were compared to each other. The changes of the investigated parameters of the spontaneous EEG were more express& in the second and the third generation. It was found that the EEGs of the treated rats after both visual and acoustical stimulations were also altered, e.g. the duration of the activated period of the exposed rats’ EEG caused by stimulation was longer; the activity of the i~+te~frcn(uanzy‘wave bands was more expressed, etc. On the basii of the study. it was stated that the biosfactrical function of the brain was significantly injured by relatfvefylow doses of organophosphorouscompounds. and this effect became more serfous. especially depending on the treated generations. ft appears to be important to take into consideration the chronic low level exposure of the human population by these widely used pesticides. Research was supported by the Hungarian OTKAgrant No l1’32B92 Key wrds:
EEG; dimethoate; diih!orvos; parathiorrnlethyf; rat
Comparison of Benchmark Doses (MD) with No-Observed- Advwa+Effect-Levels (NOAELs) and Low-Obserwxt Advers&Efkct-Levels (LOAELs) for SubchronIc lbxMty Studies R.S. Nair. MA Martens. Monsanto Cornpan)! St. Louis, MO The benchmark dose procedure has been proposed as an alternative to the NOAEL approach for non-cancer risk assessment. Two sets of evaluations have been conducted in which the NOAEL or LOAEL was compared to various benchmark doses. In the Monsanto study (Ekuta et al., The Toxicologist 14.401, 1994). the investigatorsevaluated both continuous and quanta1endpoints. In general. quanta1endpoints had lower BMDs and higher quanta1data, the NOAEL was approximated for about 50% of the studies by the BMDm. about 15% by the BMDto, and about 15% by the BMDct _ For studies with continuous data. BMD calculations based on comparison of percentage change from the mean did not provide a consistent relationshipwith NOAEL or LOAEL. In the same study, the inffuence of the number of dose levels on the BMD was evaluated. Omitting dose levels below the LOAEL dii not influence the calculation of BMD by these models while omission of a dose level producing a msponse generated lower BMDs. Shoaf et al. (The Toxicologist13. 142. 19931compared the maximum likelihood estimate and the lower bound of the 10% response level for a critical effect (quanta1data) from a series of inhalation studies to the respective NOAEL. The 10% effective concentration (ECrc) compared well with the LOAEL and the lower bound on the dose (LECtc) of 10% effecti ‘e concentration compared favorably with the NOAEL. At present, use of the BMD approach is only recommended for use with quanta1data.
Long-Term Consequences of Prenatal Exposure to Morphine: Functional Changes of the Endogenous Opioid Systems R.J.M. Niesink ’ , J.M. van Ree. Dept. of Pharmacolog): Rudolf Magnus Institute, Facuhy of Medicine, We&t Universiw, Utrecht, fhe Netherlands: ’ Dept. of Natural Sciences, Open Universiw.Heerlen. The Netherlands A number of studies suggest that brain opioid systems are involved in the regulation of play behaviour.Treatment with morphine enhances and treatment with the opioid antagonists naloxone or naltrexone depresses social play [l]. In addition. in utero exposure to morphine has a significant effect on play behaviour in juvenile animals. In the present study. pregnant Wistar rats were administered morphine subcutaneousfy (10 mg/lrg) on gestational days 7-21. The morphine treatment did not affect maternal lethality, number of pups in the litter or growth. On the day the PUPS were born mothers were replaced with drug naive experienced foster mothers. From the second day after birth until postnatal day 21, the young animals were regularlytested in a test battery to measure neuromuscular and sensory development of the animals. No differences in development of locomotion and sensory functions between morphine exposed and control animals were found in these tests. Play behaviour,as measured by pinningfrequency and duration, on days 21 and 28, was increased in the morphine exposed animals. Subcutaneous administration of 1 mgn(g morphine 1 hour before the test increased pinning in both morphine exposed and control animals. Naltrexone (1 mgkg; SC.).administered 1 hour before the test, significantlydecreased play behaviour in control rats, but not in the morphine exposed animals. From these experiments we concluded that the long term effect of in utero exposure to morphine on play behaviour is established by affecting the endogenous opiold system.
EEG; dimethoate; diih!orvos; parathiorrnlethyf; rat
Comparison of Benchmark Doses (MD) with No-Observed- Advwa+Effect-Levels (NOAELs) and Low-Obserwxt Advers&Efkct-Levels (LOAELs) for SubchronIc lbxMty Studies R.S. Nair. MA Martens. Monsanto Cornpan)! St. Louis, MO The benchmark dose procedure has been proposed as an alternative to the NOAEL approach for non-cancer risk assessment. Two sets of evaluations have been conducted in which the NOAEL or LOAEL was compared to various benchmark doses. In the Monsanto study (Ekuta et al., The Toxicologist 14.401, 1994). the investigatorsevaluated both continuous and quanta1endpoints. In general. quanta1endpoints had lower BMDs and higher quanta1data, the NOAEL was approximated for about 50% of the studies by the BMDm. about 15% by the BMDto, and about 15% by the BMDct _ For studies with continuous data. BMD calculations based on comparison of percentage change from the mean did not provide a consistent relationshipwith NOAEL or LOAEL. In the same study, the inffuence of the number of dose levels on the BMD was evaluated. Omitting dose levels below the LOAEL dii not influence the calculation of BMD by these models while omission of a dose level producing a msponse generated lower BMDs. Shoaf et al. (The Toxicologist13. 142. 19931compared the maximum likelihood estimate and the lower bound of the 10% response level for a critical effect (quanta1data) from a series of inhalation studies to the respective NOAEL. The 10% effective concentration (ECrc) compared well with the LOAEL and the lower bound on the dose (LECtc) of 10% effecti ‘e concentration compared favorably with the NOAEL. At present, use of the BMD approach is only recommended for use with quanta1data.
Long-Term Consequences of Prenatal Exposure to Morphine: Functional Changes of the Endogenous Opioid Systems R.J.M. Niesink ’ , J.M. van Ree. Dept. of Pharmacolog): Rudolf Magnus Institute, Facuhy of Medicine, We&t Universiw, Utrecht, fhe Netherlands: ’ Dept. of Natural Sciences, Open Universiw.Heerlen. The Netherlands A number of studies suggest that brain opioid systems are involved in the regulation of play behaviour.Treatment with morphine enhances and treatment with the opioid antagonists naloxone or naltrexone depresses social play [l]. In addition. in utero exposure to morphine has a significant effect on play behaviour in juvenile animals. In the present study. pregnant Wistar rats were administered morphine subcutaneousfy (10 mg/lrg) on gestational days 7-21. The morphine treatment did not affect maternal lethality, number of pups in the litter or growth. On the day the PUPS were born mothers were replaced with drug naive experienced foster mothers. From the second day after birth until postnatal day 21, the young animals were regularlytested in a test battery to measure neuromuscular and sensory development of the animals. No differences in development of locomotion and sensory functions between morphine exposed and control animals were found in these tests. Play behaviour,as measured by pinningfrequency and duration, on days 21 and 28, was increased in the morphine exposed animals. Subcutaneous administration of 1 mgn(g morphine 1 hour before the test increased pinning in both morphine exposed and control animals. Naltrexone (1 mgkg; SC.).administered 1 hour before the test, significantlydecreased play behaviour in control rats, but not in the morphine exposed animals. From these experiments we concluded that the long term effect of in utero exposure to morphine on play behaviour is established by affecting the endogenous opiold system.