In examining traditional dose-response and hormesis, we have considered the case examples of pulmonary hyperplasia following inhalation of carbon black and pulmonary hyperplasia after methyleneindolenine (3MEIN) exposures, development of irreversible pulmonary fibrosis, effect of continuous exercise and low-level lead exposures, and colorectal cancer. Adaptation can be used to estimate conventional dose responses. All cases discussed provided increased information about the reactions if hormetic features were included. In only the shigatoxin case was there clear irrefutable evidence that beneficial hormetic properties exist and must be considered; however, the one-in-six advantage is too great to ignore the potential benefits of hormesis. We recommend such hormetic properties be considered together with conventional dose responses to improve estimates of chemical risk.
We report the clinical signs and the effects on leukocyte neurotoxic esterase and red blood cell and plasma acetylcholinesterase (AChE) activities in swine orally administered a single dose of tri-o-cresyl phosphate (TOCP) at 400, 800 or 1000 mg/kg. Swine in all dosage groups exhibited signs consistent with inhibition of nervous tissue cholinesterase 3-48 h after TOCP administration. Onset was dose-related, and 2/3 1000 mg/kg dosed swine died 3 or 35 h postdosing. In surviving swine, significant depressions in plasma AChE activity were apparent at 6 h postdosing, ranging from 16-23% of predosing levels. Similar depressions of red blood cell AChE were not observed until 24 h postdosing. Plasma AChE activities appeared to more accurately reflect the development of acute cholinergic signs observed in the 1000 mg/kg dosed swine at 3 h postdosing while red blood cell AChE activities were more consistent with the delayed cholinergic signs exhibited by the 400 and 800 mg/kg dosed swine at 24 h postdosing. All survivors developed signs of delayed neurotoxicity 10-12 d after TOCP administration, and 70% or greater inhibition of neurotoxic esterase activity in leukocytes was apparent during the first 48 h postdosing.
People are exposed to a staggering assortment of chemicals and foreign substances. Potential health risks accompany these exposures. Intelligent, informed decisions are needed on which risks can and should be reduced, eliminated, or simply ignored. Therefore, a method of determining the attendant human health risks involved in chemical exposure is necessary. This need has resulted in the evolution of the risk assessment process which was developed to aid in identifying, characterizing and quantifying risks. Risk assessment today is an essential component of regulatory decision-making. In the context of chemical exposure, risk assessment is an evaluation of the risk in human exposure to chemicals in the environment. Quantitative risk assessment (QRA) is the use of experimental laboratory data and/or human epidemiological data in a process to derive a quantitative value for the estimate of the probability of harm occurring to exposed human populations. It is a sophisticated process involving an array of techniques that can be used to identify potential risks to human health. There are 4 components involved in the formalized risk assessment process--hazard identification, toxicity assessment, exposure assessment and risk characterization. These 4 steps collectively address each of 6 key areas identified as essential in characterizing a risk situation involving a chemical exposure. The process of risk estimation involves uncertainties because there are always gaps in knowledge or a lack in understanding mechanisms. These crucial gaps in knowledge are filled when extrapolations, models or assumptions are used. The uncertainties inherent in the risk assessment process are the basis of arguments against the use of the process. Many of these sources of uncertainty inherent in the risk assessment process are examined herein. These include, but are not limited to, modeling methods, understanding mechanisms and pharmacodynamics, exposure data, assumptions and extrapolations. Some new techniques and approaches being applied to the risk assessment process are examined. These include improved models for extrapolating data and quantifying risks, improved laboratory techniques for investigating pharmacodynamic and mechanistic pathways and advancements in quality and application of epidemiological data. The actual concept of uncertainty is being examined and attempts are being made to directly address, quantify and manage uncertainty.
Thirty-six steers (148 to 500 kg) divided into six equal groups were used in a toxic syndrome study of lasalocid and monensin given as a single oral dose. One group was given a placebo, a second group received monensin (25 mg/kg body weight) and the other four groups received lasalocid at 1, 10, 50 or 100 mg/kg body weight (bw). No toxic signs developed in cattle given placebo or lasalocid at 1 or 10 mg/kg bw dose. The earliest toxic signs were muscle tremors, tachycardia and rumen atony. After 24 h, the cattle were dehydrated, anorectic and had diarrhea. Deaths occurred between d 1 and 22.5 in the groups receiving lasalocid at 50 and 100 mg/kg bw and monensin. Altered values in blood leucocytes, erythrocytes, hemoglobin, hematocrit, total protein, albumin, creatinine, urea nitrogen, total bilirubin, creatine kinase, lactic dehydrogenase, calcium, chloride and inorganic phosphate occurred 1 d after dosing; urine pH and specific gravity also changed 1 d after dosing. Maximum changes occurred at d 3. Most of the changes were indicative of dehydration rather than specific organ damage.
Feeding well-mixed ionophores to adapted cattle improves ruminal fermentation and growth rates. In nonruminants, growth is improved by reducing competing gastrointestinal microorganisms. Interactions of monensin with other drugs may be beneficial or toxic. Tiamulin and furazolidone potentiate monensin's negative effects. For example, monensin produces positive inotropy and cardiomyopathy dependent on calcium and extracellular sodium. Based on available toxicity data and derived no observable effect levels (NOEL) in the same species and across species, monensin was more toxic than salinomycin, lasalocid or narasin. Lasalocid was 5- to 10-fold less toxic to horses than is monensin. Based on available toxicity data and derived NOEL, lasalocid was less toxic than all ionophores except salinomycin. Very high levels of narasin caused death in sows, leg muscle weakness in turkeys, and cardiopulmonary clinical signs in 15% of the rabbits from Brazilian rabbit farms. Only salinomycin and lasalocid were less toxic than narasin. Salinomycin was the least toxic of all the ionophores. Maduramicin was the most toxic of all the ionophores. Nearly all maduramicin fed to poultry persists in litter (manure), making this poultry litter toxic if fed to cattle as a nitrogen source. While ionophore comparative toxicity was difficult to estimate, most cross-comparisons utilized NOEL within and across species. The relative toxicities of the ionophores from lowest to highest were salinomycin < lasalocid < or = narasin < or = monensin (but lasalocid < monensin) < maduramicin.
Abstract Ten clinically normal male beagle dogs were used in the study. Two dogs served as control, 4 received 2 mg lead/kg daily and 4 received 5 mg lead/kg/daily. Lead was administered for 13 weeks, after which one‐half of each experimental group was treated with calcium ethylene diaminetetraacetate (CaEDTA) for 5 days. All animals were then monitored for another 4 weeks. Blood lead levels, haematology, blood glutathione concentration, and the number of bone marrow cells with stainable iron granules were measured weekly during the 18‐week experimental period. Clinical signs of poisoning were observed only in one dog in the high dose group after 6 weeks. The signs included emaciation, anorexia, muscular weakness, evidence of abdominal pain and depression. These signs were reversed with cessation of lead dosing and CaEDTA treatment. Blood lead levels and the number of marrow cells with non‐haeme iron increased in both lead‐dosed groups; nucleated red blood cells increased only in high lead dosed group. There was a trend for an increased packed cell volume in all groups; however, the high lead dosed group did not increase as fast. No significant changes were observed in blood glutathione concentration and in other haematologic parameters. There were no differences in the parameters studied between the dogs treated with CaEDTA and those not so treated. Blood lead levels and the number of nucleated red blood cells decreased after cessation of lead administration and the number of marrow cells with iron also tended to decrease after lead removal.
