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K K Rozman

Publications and source records attributed to K K Rozman.

At least 19 recordsLinked to original sources
PubMed2002

Comments on the Jayjock et al. paper.

Establishing hormesis as an evolution-based biological phenomenon requires a broad discussion of its implications for currently used risk paradigms. The Jayjock et al. papers provide an industrial hygienist's perspective and, as such, represent a valuable contribution to this discussion. Our comments outline a toxicologist's view on the limits and practicability of the Jayjock et al. suggestions. The arguments are primarily based on the shape of dose and time responses and associated variabilities and uncertainties.

Animals↗
PubMed2001

Paracelsus, Haber and Arndt.

After a brief overview of the contributions of Paracelsus, Haber and Arndt to the theory of toxicology, examples are provided for quantitative risk/safety assessments using dose (c), time (t) and effect (E) as macroscopic variables of toxicity. The discussion offers explanations for application of the decision tree approach in identifying rate-determining steps in the toxicity of chemicals. Having done so allows for reasonably accurate predictions of cancer incidence (bladder, liver, heart, histiocyte) using Haber's Product under isoeffective conditions and the equation cxt=kxE for isodosic and isotemporal responses.

Dose-Response Relationship, Drug↗
PubMed2001

A review of mechanisms controlling ovulation with implications for the anovulatory effects of polychlorinated dibenzo-p-dioxins in rodents.

Polychlorinated dibenzo-p-dioxins (PCDDs) can impinge on female fertility by preventing ovulation. In this review, the aspects of normal ovulatory physiology most relevant to our current understanding of PCDD action on the ovary are briefly reviewed. This is followed by a comprehensive assessment of data relevant to the effects of PCDDs during ovulation in the rat. PCDDs interrupt ovulation through direct effects on the ovary in combination with dysfunction of the hypothalamo-hypophyseal axis.

Animals↗
PubMed2001

2,3,7,8-tetrachlorodibenzo-p-dioxin decreases responsiveness of the hypothalamus to estradiol as a feedback inducer of preovulatory gonadotropin secretion in the immature gonadotropin-primed rat.

Sprague-Dawley rats (23-day-old) were dosed with TCDD (32 microg/kg) in corn oil or vehicle alone. Equine chorionic gonadotropin (eCG) was injected (5 IU, sc) 24 h later to induce follicular development. Another 24 h later, half of TCDD- or corn oil-treated rats were injected (sc) with 17 beta-estradiol-cypionate (ECP, at 0.004 to 0.5 mg/kg). Blood and ovaries were collected on expected proestrous (preovulatory period) at 51, 54, and 58 h after eCG injection as well as in the morning after ovulation (72 h after eCG). Serum concentrations of 17 beta-estradiol (E), progesterone (P), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were determined by radioimmunoassay. The number of ova shed was measured at 72 h after injection of eCG by irrigating ova from oviducts. During the preovulatory period (approximately 58 h after eCG injection), a circulating level of 70-100 pg E/ml coincided with LH and FSH surges and later normal ovulation of 10 to 12 ova/rat was observed in controls. However, the same concentration of E was not associated with LH and FSH surges in rats treated with TCDD (32 microg/kg), resulting in reduced ovarian weight gain and reduction of ovulation by 70 to 80% (2-3 ova/rat). Blockage of the gonadotropin surge, reduced ovarian weight gain, and ovulation were all reversed completely by the lowest effective dose of ECP (0.1 mg/kg). At 72 h after eCG, serum P secretion was reduced and serum E levels were significantly increased compared to those of corn oil-treated controls. ECP alone had no effect on serum P levels at any time point, but in rats treated with TCDD and ECP, both the reduction of P (at 58 and 72 h) and the increase in E secretion (72 h) were completely reversed. Further studies confirmed that restoration by ECP of gonadotropin surges and associated ovulation could not be attained until circulating levels of E rose sufficiently high to trigger the LH and FSH surges. The new action threshold of E for inducing gonadotropin surges in rats treated with TCDD (32 microg/kg) was determined to be eight- to 10-fold higher than that in controls. Thus, it is apparent that TCDD decreased the responsiveness of the hypothalamus to E as a feedback inducer of preovulatory gonadotropin secretion.

Animals↗
PubMed2001

Kinetics of monochloroacetic acid in adult male rats after intravenous injection of a subtoxic and a toxic dose.

Distribution, metabolism, and excretion of monochloroacetic acid (MCA) were examined in adult male rats at a subtoxic (10 mg/kg) and a toxic (75 mg/kg) dose. Rats were injected i.v. with [14C]MCA and housed individually. Urine and feces were collected. Animals were euthanized at different time intervals after dosing and tissues procured. Radioactivity in aliquots showed very rapid distribution of MCA to tissues. Concentrations of MCA in plasma, liver, heart, lungs, and brown fat paralleled each other, whereas those in brain and thymus did not. There was no dose proportionality in tissue concentrations. Elimination of MCA from plasma required modeling by two compartments. Most of the radioactivity found in plasma was parent MCA. Elimination rate constant (K(10)) and distribution rate constant (K(12)) were greatly reduced at the toxic dose. Elimination of the toxic dose was further retarded due to increased retention of MCA in the peripheral compartment as indicated by increased mean residence times in most tissues. A very large fraction of dose was found in the gastrointestinal tract, almost all of which was reabsorbed. Attempts to reduce toxicity by blocking the enterohepatic circulation with activated charcoal or cholestyramine failed. Radioactivity found in bile was associated with one metabolite more polar than the parent compound. A very large fraction of dose (73 and 59%) was found in urine, 55 to 68% of which was parent MCA. The rate-determining step in the toxicity of MCA was identified as its detoxification by the liver. A therapeutic approach in MCA intoxications is suggested.

Acetates↗
PubMed2001

The role of time as a quantifiable variable of toxicity and the experimental conditions when Haber's c x t product can be observed: implications for therapeutics.

One hundred years ago, Warren established for the first time a quantitative link between dose and time while studying the toxicity of sodium chloride in Daphnia magna (Straus). During this century, many toxicologists in different contexts returned to this idea, which has become known as Haber's Rule of inhalation toxicology. Most attempts to explore this relationship ended in frustration because of the observed deviations from it, which were unfortunately called exceptions. Thus, toxicologists concentrated on the quantitative relationship between dose and effect under mostly isotemporal conditions, while time was assigned such arbitrary, semiquantitative designations as acute, subacute, subchronic, and chronic. Time itself as a quantifiable variable of toxicity was seldom studied and when it was examined, it was often not done under isodosic (steady-state) conditions. A recent analysis of time as a variable of toxicity indicated the existence of at least three independent time scales (toxicokinetic, toxicodynamic, exposure frequency/duration) in toxicological studies, which interact with dose and effect to yield the enormous complexity known to every toxicologist. Based on prototypical examples when toxicokinetic (dioxins, chloroacetic acid), toxicodynamic (nitrosamines, soman, sarin, tabun), exposure frequency (methylene chloride), or other experimental design-related conditions (HgCl(2), CdCl(2)) represent the critical time scale, the general validity of the c x t = k concept will be discussed as a starting point for a theory of toxicology. As endpoints of toxicity, (delayed) acute toxicity, blood dyscrasias, and cancer will be used to illustrate the critical conditions needed to demonstrate the validity of this theory. The relevance of this theory to the pharmacologic action of chemicals and its implication for the therapeutic index are also discussed.

Acetates↗
PubMed2000

Occupational exposure limits for 30 organophosphate pesticides based on inhibition of red blood cell acetylcholinesterase.

Toxicity and other relevant data for 30 organophosphate pesticides were evaluated to suggest inhalation occupational exposure limits (OELs), and to support development of a risk assessment strategy for organophosphates in general. Specifically, the value of relative potency analysis and the predictability of inhalation OELs by acute toxicity measures and by repeated oral exposure NOELs was assessed. Suggested OELs are based on the prevention of red blood cell (RBC) acetylcholinesterase (AChE) inhibition and are derived using a weight-of-evidence risk assessment approach. Suggested OEL values range from 0.002 to 2 mg/m(3), and in most cases, are less than current permissible exposure levels (PELs) or threshold limit values(R) (TLVs(R)). The available data indicate that experimental data for most organophosphates evaluated are limited; most organophosphates are equally potent RBC AChE inhibitors in different mammalian species; NOELs from repeated exposure studies of variable duration are usually equivalent; and, no particular grouping based on organophosphate structure is consistently more potent than another. Further, relative potency analyses have limited usefulness in the risk assessment of organophosphates. The data also indicated that equivalent relative potency relationships do not exist across either exposure duration (acute vs. repeated) or exposure route (oral vs. inhalation). Consideration of all variable duration and exposure route studies are therefore usually desirable in the development of an OEL, especially when data are limited. Also, neither acute measures of toxicity nor repeated oral exposure NOELs are predictive of weight-of-evidence based inhalation OELs. These deviations from what is expected based on the common mechanism of action for organophosphates across exposure duration and route - AChE inhibition - is likely due to the lack of synchrony between the timing of target tissue effective dose and the experimental observation of equivalent response. Thus, comprehensive interpretation of all toxicity data in the context of available toxicokinetic, toxicodynamic and exposure information for each individual organophosphate in a weight-of-evidence based risk assessment is desirable when deriving inhalation OELs.

Animals↗
PubMed2000

The role of time in toxicology or Haber's c x t product.

It happened exactly 100 years ago that Warren established for the first time a quantitative link between dose and time while studying the toxicity of sodium chloride in Daphnia magna (Straus). During this century many toxicologists in different contexts returned to this idea, which has become known as Haber's rule of inhalation toxicology. Most attempts to explore this relationship ended in frustration because of the supposed occurrence of exceptions. Thus, toxicologists concentrated on the quantitative relationship between dose and effect under mostly isotemporal conditions while time took a back seat and was assigned such arbitrary, semiquantitative designations as acute, subacute, subchronic and chronic. Time itself as a quantifiable variable of toxicity was seldom studied and when it was studied, it was often not under isodosic (steady state) conditions as required by theory. A recent analysis of toxicological time indicated the impact of three independent time scales (toxicokinetic, toxicodynamic, exposure frequency/duration) in toxicological studies, which interact with dose and effect to yield the enormous complexity known to every toxicologist. Based on prototypical examples when toxicokinetic (dioxins), toxicodynamic (nitrosamines, benzene) or exposure frequency (methylene chloride, chloroacetic acid, HgCl(2), CdCl(2), etc.) represent the critical time scale, the general validity of the c x t=k concept will be discussed as a starting point for a theory of toxicology. As endpoints of toxicity, (delayed) acute toxicity, blood dyscrasias and cancer will be used to illustrate the critical conditions needed to demonstrate the validity of this theory.

Animals↗
PubMed2000

Gonadotropin-releasing hormone (GnRH) partially reverses the inhibitory effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin on ovulation in the immature gonadotropin-treated rat.

Several studies have shown that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has inhibitory effects on ovulation. This action may be the result of either direct effect(s) of TCDD on ovarian function or via altered secretion of pituitary luteinizing hormone (LH) and follicle stimulating hormone (FSH) which regulate ovarian follicular development and ovulation. To further evaluate the effects of TCDD on pituitary gonadotropins and their regulation, the potential role of gonadotropin-releasing hormone (GnRH) was investigated in the current study. Immature (23-day-old) female Sprague-Dawley rats were dosed with TCDD (32 microg/kg) in corn oil or vehicle alone. Equine chorionic gonadotropin (eCG) was injected subcutaneously (5 IU, sc) 24 h later to induce follicular development. Immediately prior to the expected time of the LH/FSH surges, 54 h after eCG injection, half of TCDD- or corn oil-treated rats were injected with GnRH (2 microg/rat, sc). Blood and ovaries were collected at 54, 56, 58, 60 and 72 h after eCG. Serum concentrations of 17beta-estradiol (E(2)), progesterone (P(4)), LH, and FSH were determined by radioimmunoassay. An indication of ovulation rate was assessed at 72 h after injection of eCG by irrigating the ova from oviducts. TCDD reduced the number of ova in the oviducts by 70-80% (2-3 ova/rat) and this was confirmed by the number of corpora lutea. GnRH partially restored ovulation (6-7 ova/rat) in TCDD-treated rats without reversing its effect on ovarian weight reduction. In controls, the LH and FSH surges at 58 h after eCG were significantly reduced at that time in TCDD-treated rats. However, in rats treated with TCDD and GnRH, a huge LH/FSH surges occurred at 56 h after eCG injection. GnRH alone enhanced E(2) and P(4) serum levels at 56-58 h after eCG injection. In rats treated with both TCDD and GnRH, E(2) secretion was significantly lower at 58, 60, and 72 h when compared with GnRH alone, whereas serum P(4) was only decreased at 72 h after eCG injection. The results indicate that exogenous GnRH induces LH and FSH surges in TCDD-treated rats, but only partially restores the inhibitory effects of TCDD on ovulation.

Animals↗
PubMed2000

Dose and time as variables of toxicity.

Recognizing that if there is no exposure, there is no toxicity leads us to the conclusion that if there is exposure, toxicity can ensue when exposure exceeds a certain dose and/or time and that it will be dependent on toxicokinetics and toxicodynamics. Analysis of the fundamental description of toxicity (dT/dE=dT/dDxdD/dKxdK/dE, where T stands for toxicity, D for toxicodynamics, K for toxicokinetics and E for exposure) yields the recognition of three independent time scales, the first being an intrinsic property of a given compound (what does the chemical do to the organism), which is the dynamic time scale. The second time scale is an intrinsic property of a the organism (what does the organism do to the chemical), which represents the kinetic time scale. The frequency of exposure denotes the third time scale, which is independent of the dynamic and kinetic time scales. Frequency of exposure depends on the experimental design or on nature, but not on the organism or substance. A liminal condition occurs when the frequency becomes so high that it is indistinguishable from continuous exposure. Continuous exposure forces the two other time scales to become synchronized thereby reducing complexity to three variables: dose, effect and one time scale. Keeping one of those variables constant allows for the study of the other two variables reproducibly under isoeffective or isodosic or isotemporal conditions. However, any departure from continuous exposure will introduce the full complexity of four independent variables (dose and kinetic, dynamic and frequency time scales) impacting on the effect (dependent variable) at the same time. The examples discussed in this paper demonstrate how nature in the form of long half-lives provides liminal conditions when either kinetic or dynamic half lives force synchronization of all three time scales. However, for compounds having very short dynamic or kinetic half-lives, only continuous exposure will provide a synchronized time scale. A decision tree-type approach is being used to illustrate how to reduce the enormous complexity generated by five variables (dose, effect and up to three time scales) in toxicology to manageable proportions by identifying and modeling the rate-determining (-limiting) step(s) in the manifestation of toxicity.

Algorithms↗
PubMed2000

Effects of polychlorinated dibenzofurans, biphenyls, and their mixture with dibenzo-p-dioxins on ovulation in the gonadotropin-primed immature rat: support for the toxic equivalency concept.

Previous studies have shown that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 1,2,3,7,8-pentachlorodibenzo-p-dioxin (PeCDD), and 1,2,3,4,7, 8-hexachlorodibenzo-p-dioxin (HxCDD), and their equipotent mixture block ovulation, reduce ovarian weight gain and alter preovulatory hormone levels in a similar manner. The objective of the current experiment was to investigate the effect of other structurally related compounds such as chlorinated furans and biphenyls on ovulation and related hormonal endpoints. The gonadotropin-primed immature female rat model was used to study the effect of 2,3,4,7, 8-pentachlorodibenzofuran (PeCDF), 3,3',4,4',5-pentachlorobiphenyl (PeCB), and 2,2',5,5' tetrachlorobiphenyl (TCB) and their mixture with polychlorinated dibenzo-p-dioxins (PCDDs) on ovulation. Rats were dosed on Day 23 of age at 0900 h with individual congeners (PeCDF, PeCB, TCB) or a mixture of five compounds, which included TCDD, PeCDD, HxCDD, in addition to PeCDF and PeCB. Equine choronic gonadotropin (eCG; 5 IU) was injected 24 h later to induce follicular development. Blood and ovaries were harvested, and ovarian weights determined at various times after eCG. Serum concentrations of 17beta-estradiol (E(2)), progesterone (P(4)), luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were determined by radioimmunoassay. At 72 h after injection of eCG, the number of ova shed was measured by irrigating the ova from oviducts. The slopes of the dose-responses for inhibition of ovulation generated by the individual PeCDF, PeCB, and/or their mixture with PCDDs were similar. PeCDF, PeCB, and the mixture increased serum concentrations of E(2) at 72 h after eCG injection, the day of expected ovulation; in contrast, serum P(4) and FSH were decreased at that same time point. Only the high doses of TCDD, PeCDF, and PeCB blocked LH and FSH surges at 58 h after eCG. The ovarian histology revealed that the effects of PeCDF, PeCB, and the mixture were very similar to those of PCDDs, consisting of ova in large preovulatory follicles and a lack of or reduced number of corpora lutea. Parallel dose-responses of the individual congeners (PeCDF and PeCB) and their equipotent mixture with PCDDs support the toxic equivalency (TEQ) concept for the blockage of ovulation. Thus, PCDDs, PCDFs, and PeCBs appear to block ovulation by the same or a very similar mechanism of action.

Animals↗
PubMed1999

Toxic equivalency factors of polychlorinated dibenzo-p-dioxins in an ovulation model: validation of the toxic equivalency concept for one aspect of endocrine disruption.

Polychlorinated dibenzo-p-dioxins (PCDDs) are structural analogues, which produce a similar spectrum of biological and toxicological responses in animals, albeit with differential potencies. Very consistent structure-activity relationships have been found for acute toxicity and some biochemical effects among these compounds. For the current experiments, the gonadotropin-primed immature female rat model was used to study the effect of 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD), 1,2,3,7, 8-pentachlorodibenzo-p-dioxin (PeCDD), and 1,2,3,4,7, 8-hexachlorodibenzo-p-dioxin (HxCDD) on ovulation. Single doses of different PCDDs and their mixture were given orally to 23-day-old rats. Gonadotropin from pregnant mare's serum (PMSG) was injected (5 IU) 24 h later to induce follicular maturation. Rats were decapitated at various times after PMSG, blood was collected, and ovarian weight was measured. Serum concentrations of 17beta-estradiol (E2), progesterone (P4), luteinizing hormone (LH), follicle stimulating hormone (FSH), and prolactin (PrL) were determined by radioimmunoassay. Ovulation was measured at 72 h after injection of PMSG by counting ova flushed from oviducts. PCDDs dose dependently decreased the number of ova per ovary and reduced ovarian weight gain induced by PMSG. The slopes of the dose-response curves generated by individual PCDDs and/or their mixture were similar. PMSG-induced increase in serum E2 was enhanced on the day of expected ovulation by PCDDs; in contrast, serum P4 and FSH were decreased at that same time point. PCDDs also altered the temporal pattern of serum E2, FSH, and LH but not that of PrL. Histologically the effect of all three PCDDs consisted of ova trapped in preovulatory follicles and a lack of or reduced number of corpora lutea. The results indicate that the PCDDs, tested in the present model, have the same mode of action on ovulation and the reproductive hormones, e.g., LH, FSH, P4 and E2. Furthermore, the dose responses of the individual congeners are parallel to each other and also to that of their equipotent mixture, which represent a validation of the TEQ concept for one aspect of endocrine disruption, that is for inhibition of ovulation.

Animals↗
PubMed1999

Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on liver phosphoenolpyruvate carboxykinase (PEPCK) activity, glucose homeostasis and plasma amino acid concentrations in the most TCDD-susceptible and the most TCDD-resistant rat strains.

Reduced gluconeogenesis due to decreased activity of key gluconeogenic enzymes in liver, together with feed refusal, has been suggested to play an important role in 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD)-induced lethality in rats. This study was carried out to further analyse the toxicological significance of reduced gluconeogenesis by comparing dose-responses and time-courses of effects of TCDD on the activity of phosphoenolpyruvate carboxykinase (PEPCK) in liver, liver glycogen concentration as well as plasma concentrations of glucose and amino acids in both genders of TCDD-sensitive Long-Evans (L-E) rats and TCDD-resistant Han/Wistar (H/W) rats. A dose-dependent decrease in PEPCK activity was observed in H/W rats, but in L-E rats the activity was not decreased. However, TCDD impaired the strong increase in liver PEPCK activity observed in pair-fed controls of the L-E strain. Liver glycogen concentrations were severely decreased in L-E rats and moderately in H/W rats. This effect seems to be secondary to reduced feed intake, since a similar decrease was seen in pair-fed controls. Decreases in plasma glucose concentrations were also more profound in L-E rats than in H/W rats, but pair-fed controls were generally less affected. Circulating concentrations of amino acids were markedly increased in TCDD-treated L-E rats, which is likely to reflect increased mobilization of amino acids and their decreased metabolism in liver. Reduction of liver PEPCK activity cannot account for the sensitivity difference of these two strains of rats in terms of mortality. Nevertheless, the response of both strains of TCDD-treated rats regarding gluconeogenesis is different from that seen in pair-fed controls and suggesting that impairment of this pathway contributes to the development of the wasting syndrome.

Amino Acids↗
PubMed1999

Delayed acute toxicity of 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HpCDD), after oral administration, Obeys Haber's rule of inhalation toxicology.

Eight different doses (2.5 to 10.0 mg/kg) of 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (HpCDD) were administered acutely to a total of 272 female Sprague-Dawley rats. The doses ranged from a NOAEL for wasting/hemorrhage to supralethal doses. Dose- and time-responses of wasting/hemorrhage, anemia, and cancer were and are being studied as end points of toxicity. The experiments will be continued until the last rat dies. There was a very steep dose- and time-response between the LOAEL for wasting/hemorrhage (2.8 mg/kg) and the third highest dose (4.1 mg/kg) of HpCDD. The dose-and time-responses were nearly symmetrical, obeying Haber's Rule of inhalation toxicology (c x t = constant) even beyond 100% mortality. Introduction of a minimum of 25% body weight loss as a discriminatory criterion to separate wasting from hemorrhage as the primary cause of death reduced variability from 5.8 to 3.2%. An arithmetic plot of the dose and time data resulted in a nearly perfect hyperbola. A logarithmic plot of these data yielded a straight line of similar perfection. Dose-response data at constant times illustrate the shifting of the dose-response curve towards a liminal value, which represents the necessary observation period for this effect. Time-response data at constant doses demonstrate the shifting of the time-response curve towards a liminal value, which represents the LOAEL for the dose-response of this effect. A three-dimensional plot of dose- and time-response data depicts the surface area on which c x t is constant along hyperbolas, in terms of wasting as the end point of toxicity. Surviving rats in all groups started developing anemia 126 days after dosing, but no rat died of wasting/hemorrhage after day 74. Rats surviving anemia began to die of lung cancer as of day 397 after dosing. Thus, although the experiment has been completed as far as dose- and time-responses of wasting/hemorrhage are concerned, it will be about another 2 years before complete dose and time responses will become available for anemia and lung cancer.

Anemia↗
PubMed1998

Derivation of an occupational exposure limit (OEL) for methylene chloride based on acute CNS effects and relative potency analysis.

The Occupational Safety and Health Administration (OSHA) methylene chloride Permissible Exposure Level (PEL) or 25 ppm is quantitatively derived from mouse tumor results observed in a high-exposure National Toxicology Program bioassay. Because this approach depends on controversial interspecies and low-dose extrapolations, the PEL itself has stimulated heated debate. Here, an alternative safety assessment for methylene chloride is presented. It is based on an acute human lowest-observed-adverse-effect level (LOAEL) of 200 ppm for subtle central nervous system (CNS) depression. Steep, parallel exposure-response curves for anesthetic and subanesthetic CNS effects associated with compounds mechanistically and structurally related to methylene chloride are shown to support a safety factor of two to account for inter-individual variability in response. LOAEL/no-observed-adverse-effect ratios for subtle CNS effects associated with structurally related solvents are shown to support a safety factor range of two to four to account for uncertainty in identifying a subthreshold exposure level. Anesthetic relative potencies and anesthetic/subanesthetic effect level ratios are shown to be constant for the compounds evaluated, demonstrating that subanesthetic relative potencies are also constant. Relative potencies among similarly derived occupational exposure limits (OELs) for solvents structurally related to methylene chloride are therefore used to validate the derived methylene chloride OEL range of 25-50 ppm. Because this safety assessment is based on human (rather than rodent) data and empirical (rather than theoretical) exposure-response relationships and is supported by relative potency analysis, it is a defensible alternative to to the OSHA risk assessment and should positively contribute to the debate regarding the appropriate basis and value for a methylene chloride PEL.

Anesthetics↗
PubMed1998

Subchronic/chronic toxicity of a mixture of four chlorinated dibenzo-p-dioxins in rats. I. Design, general observations, hematology,and liver concentrations.

Groups of 20 male and 20 female rats were administered five different doses of a mixture of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 1,2,3,7,8-pentaCDD (PCDD), 1,2,3,4,7,8-hexaCDD (HxCDD), and 1,2,3,4,6,7,8-heptaCDD (HpCDD). Doses were selected based on relative potency factors derived from acute toxicity data and a previous subchronic study with HpCDD. The mixture was constituted such that each of the congeners contributed one fourth to total toxic equivalency. Total doses were divided into four daily loading doses and six biweekly maintenance doses. The highest total dose for males was 17.5 microg/kg of TCDD, 87.5 microg/kg of PCDD, 350 microg/kg of HxCDD, and 2500 microg/kg of HpCDD. Positive controls were administered PCDD (350 microg/kg) or HxCDD (1400 microg/kg). Females were given 1.5 times lower doses than males. The dosing period was 13 weeks, after which half of the rats were necropsied and the rest provided with an off-dose period of another 13 weeks. Liver concentrations as determined by GC-MS reflected the doses administered. Body weight gain was dose-dependently reduced throughout the study. Mortality rates at the end of the off-dose period were 80 and 60% for the two highest dosages (mixture) in males and 70 and 10% for females. Clinical signs and necropsy findings suggested that the cause of death was related to wasting, hemorrhage, and anemia. Prothrombin times were prolonged and platelet counts were decreased in some rats receiving high doses. This study provides in vivo support for the validity of the assumption of additive toxicity of CDDs as currently used in the toxicity equivalency factor approach to assess the toxicity of mixtures of CDDs.

Administration, Oral↗
PubMed1998

Subchronic/chronic toxicity of a mixture of four chlorinated dibenzo-p-dioxins in rats. II. Biochemical effects.

Groups of 20 male and 20 female rats were given five different oral doses of a mixture of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 1, 2,3,7,8-pentaCDD, (PCDD) 1,2,3,4,7,8-hexaCDD (HxCDD), and 1,2,3,4,6, 7,8-heptaCDD (HpCDD) divided into four daily loading doses and six biweekly maintenance doses. PCDD and HxCDD were used as positive controls. The dosing period was 13 weeks, after which half of the rats were necropsied and the rest provided with an off-dose period of another 13 weeks. Liver ethoxyresorufin O-deethylase (EROD) activity was dose-dependently increased in rats dosed with the mixture starting at the lowest dose (13- to 16-fold increase), with the effect reaching maximum at the middle dosage (74- to 112-fold increase), as well as in the positive control groups. There was some indication of reversibility at the lower doses and in positive controls during the off-dose period. The activity of phosphoenolpyruvate carboxykinase (PEPCK) in liver was dose-dependently decreased (maximally by 51%). This effect was more distinct in males than in females. Liver tryptophan 2,3-dioxygenase (TdO) activity decreased maximally by 53% at the two highest doses. This effect was more distinct in females than in males. Serum tryptophan concentrations were increased in rats moribund due to wasting. Some reversibility was apparent by the end of the off-dose period regarding all three biochemical markers of CDD toxicity. Serum glucose concentrations were decreased at the three highest doses of the mixture and in positive controls, maximally by 30%, with some reversibility during the off-dose period. There was a dose-dependent decrease of serum thyroxine (T4) concentrations in rats given the mixture and in the PCDD and HxCDD dosage groups (maximally by 69%), with some reversibility in males during the off-dose period. Serum triiodothyronine (T3) levels were not much affected, except that they tended to be decreased in rats moribund with hemorrhage or anemia. The results demonstrate that comparable biochemical changes occur after multiple as after single dosing with CDDs and that TEFs derived from acute studies can be used to predict the toxicity of mixtures of CDDs regardless whether they are administered as single compounds or as a mixture. This study supports the validity of the toxic equivalency factor (TEF) method and the notion of additive toxicity for CDDs as currently used in the risk assessment of these compounds.

Administration, Oral↗