Search

The effects of lead on growth in female rats and on growth and skeletal development in their offspring were investigated. No alteration in growth rate, compared to the growth rate in pair-fed controls, was observed in 48 weanling females continuously exposed to 250 or 1000 ppm lead in drinking water and fed a replete diet. After 49 days of exposure, all rats (24 pair-fed controls, 12 exposed to 250 ppm lead, and 12 exposed to 1000 ppm lead) were mated with control males. At parturition, six lactating dams each from the 250 and 1000 ppm lead groups were removed from lead exposure and given control drinking water, and six lactating dams each from the control group were given either 250 or 1000 ppm lead in drinking water. Exposure conditions for the remaining dams in the control, 250, and 1000 ppm groups were not changed. Maternal blood lead in the continuously lead-exposed groups was higher at the end of lactation than prior to mating. Lead exposure prior to parturition caused greater maternal tibial lead accumulation than lead exposure after parturition. In contrast, lead exposure prior to parturition had a lesser impact on offspring tibial lead accumulation than lead exposure after parturition. Decreases in tibial calcium and phosphorus were observed in dams exposed continuously to 250 or 1000 ppm lead; however, there was no apparent effect of lead on maternal growth-plate morphology or on growth-plate width. Offspring body weight was depressed relative to controls during suckling (Day 11) and after weaning (Day 24) in high-dose and continuously lead-exposed groups. Continuous lead exposure caused a greater decrease in offspring body weight than lead exposure only prior to or after parturition. Decreased tail length growth suggested possible effects of lead on tail vertebral bone growth. While tibial calcium and phosphorus levels were not changed in the weanlings, increased weanling growth-plate width, with disruption of chondrocyte organization, and wider metaphyseal trabeculae were observed. Although the mechanisms of these effects are not known, the results suggest that local lead-related effects on growth-plate chondrogenesis and metaphyseal mineralization may be involved.

This study provided an assessment of the effects of lead on early growth in rats based on structural equation modeling and nested analysis of variance (ANOVA). Structural equation modeling showed that lead in drinking water (250, 500, or 1000 ppm) had a direct negative effect on body weight and tail length (i.e., growth) in female rats during the first week of exposure. During the following 2 weeks of exposure, high correlation between growth measurements taken over time resulted in reduced early postnatal growth. By the fourth week of exposure, reduced growth was not evident. Mating began after 8 weeks of exposure, and exposure continued during gestation. Decreased fetal body weight was detected when the effects of litter size, intrauterine position, and sex were controlled in a nested ANOVA. Lead exposure did not appear to affect fetal skeletal development, possibly because lead did not alter maternal serum calcium and phosphorus levels. The effect of lead on individual fetal body weight suggests that additional studies are needed to examine the effect of maternal lead exposure on fetal development and early postnatal growth.

A model of lead disposition in humans has been developed. In addition to liver, kidney, other well-perfused and poorly perfused tissues, the model incorporates bone as an explicit compartment whose volume, composition, and metabolic activity are all age-dependent. The rates of all transfers of lead out of the blood are related to plasma lead. The relationship between plasma lead and blood lead is expressed as a capacity-limited binding associated with the erythrocyte. Interchanges of lead between plasma and bone are modeled as partially interactive events linked in series. Blood traversing the bone passes first through a surface region of rapid exchange before entering the metabolically active region of bone, where lead is incorporated with calcium into mineralizing bone and returned to the blood with resorbing bone. After leaving the larger vessels, plasma superfusate enters the canalicules that feed bulk bone, where lead diffuses radially outward into the total bone volume. Model simulations are compared with data from epidemiologic and experimental dietary and inhalation studies in adults.

Realistic modeling of lead kinetics requires both qualitative and quantitative understanding of bone metabolism. In this paper, bone metabolism is discussed based on the behavior of Ca, Sr, and Ra tracers. Apposition, the increase of mineral volume, is the chief feature of bone metabolism in the neonatal and young animal. Resorption, which together with apposition functions to model the growing skeleton, is also important during growth. In adulthood, with stabilization of the total bone mass, resorption balances apposition at a relatively low level. This continuing low-level resorption/apposition remodeling process maintains healthy bone and restructures the bone in response to changing functional demands. In addition to these processes, surface exchange and diffuse exchange occur in bone. Rapid exchange between blood and bone calcium (or tracer) takes place at all bone surfaces in intimate contact with blood. Diffuse exchange is a slow process by which bone-seeking elements can penetrate the entire bone volume. Particularly in longer-lived animals like humans, slow exchange of tracer with bone Ca is the dominant mechanism of tracer uptake during adulthood. These three mechanisms of uptake and loss (apposition/resorption, rapid exchange, and diffuse exchange) appear to be the essential mechanisms determining metabolism of bone-seeking elements. The magnitudes of accretion plus rapid exchange, of resorption, and of diffuse exchange have been estimated with the aid of radiotracers and fluorescent markers.

A physiologically based toxicokinetic model of gestation in the rat and mouse has been developed. The model is superimposed on the normal growth curve for nonpregnant females. It describes the entire gestation period including the period of organogenesis. The model consists of uterus, mammary tissue, maternal fat, kidney, liver, other well-perfused maternal tissues, and other poorly perfused maternal tissues, embryo/fetal tissues, and yolk sac and chorioallantoic placentas. It takes into account the growth of maternal tissues such as uterus, mammary glands, fat, and liver during pregnancy, as well as growth of the conceptus. The gestation model is based on published values of organ volumes and blood flows for the rat throughout pregnancy. It is scaled to the mouse using conventional scaling procedures. Its descriptive utility has been examined with the test chemical 5,5'-dimethyloxazolidine-2,4-dione (DMO), a weak acid that is not bound measurably in plasma or tissues and is eliminated by excretion in the urine. Concentrations of DMO were monitored in maternal rat and embryo plasma and in homogenates of maternal rat muscle and whole embryo after ip administration at 9:00 AM on Day 13 of gestation. On the basis that distribution of DMO is determined solely by its pK and the pH's of body fluids, pH and excretion rate values were estimated by visual optimization of model predictions to the concentration profile. Successful prediction of concentrations of DMO in the same tissues of pregnant mice after its ip administration at 9:00 AM on Day 10 or 11 of gestation required only adjustment for pH's of mouse body fluids.

A review of features of bone structure and bone growth critical to the development of a physiologically based model of the whole-body kinetics of bone-seeking elements is presented. Allometric equations describing the volume and weight of the bone, bone marrow, and skeleton during growth of the rat from birth to maturity are derived. Weights of body calcium and bone ash are also expressed allometrically as functions of body weight during growth. The simplicity of these functions will allow them to form the basis of a flexible model of the movement of bone-seeking elements in and out of bone. Blood flow rates to bone and bone marrow are incorporated into the model of the mature skeleton. The predictions of the skeletal growth model are in good agreement with measured quantities of bone, skeletal ash, and calcium in growing rats.

For toxicants with long residence times in the body, body burden is determined largely by exposure history rather than by current exposure. There is a need for physiologically based toxicokinetic models capable of integrating exposure over time by incorporating growth, development, and aging. Such a model is presented for lead kinetics in the growing rat from birth to adulthood. The model incorporates age dependence of the physiologic and metabolic processes that control lead distribution to bone and soft tissues, as well as age dependence of lead absorption from the gastrointestinal tract and age dependence of elimination of lead. The essential features of bone structure and metabolism are integrated into a framework that determines bone lead kinetics. Parameter values used in the model are taken from the literature or are estimated from the best visual fit of the model to data from chronic and short-term studies of lead exposure in rats. The model accommodates any pattern of lead exposure. The uptake of lead by bone varies with the age at which exposure occurs. The predictions of the model are compared with data from a chronic study in rats in which lead exposure was discontinued after exposure periods varying from 3 to 12 months.

A model of skeletal and bone growth for the human from birth to maturity has been developed. Dry and hydrated bone, bone marrow, ash, and calcium are included in the model. Growth of the skeleton and its fractions is expressed as a set of allometric equations relating fraction volume or weight to body weight. Blood flow rates to mature bone and bone marrow are scaled from experimentally determined values in smaller animals, but bone and marrow volumes and growth patterns cannot be scaled directly from measurements or models in small animals. The growth model compares well with measured bone weights, ash weights, and bone and skeletal densities in humans. Its form is adaptable to physiologically based description of the kinetics of bone-seeking elements.

The effect of treatment of pregnant C57BL/6J (B6) and AKR/J (AKR) mice with the cytochrome P-450 inducing agent beta-naphthoflavone (beta NF) on caffeine metabolism and on exposure of dam and embryo to caffeine and to its metabolites theophylline (TP), theobromine (TB), paraxanthine (PX), and trimethyluric acid (TMUA) was investigated. Treated dams were given either 20 or 80 mg beta NF/kg ip on Days 9 and 10 of gestation. Caffeine, 175 mg/kg, was given ip on Days 11 and 12 of gestation. Concentrations of caffeine and its metabolites were monitored in maternal plasma and in embryo homogenates at 0.083, 0.25, 0.5, 1, 2, 4, and 6 hr after the second caffeine injection. Effective exposure was expressed as the area under the concentration-time curve from 0 to 6 hr. Caffeine loss in B6 mice was best described by an expression incorporating capacity-limited kinetics. Pretreatment induced formation of TB and PX, while it induced elimination of all three of the monodemethylated metabolites, in B6 mice. Consequently, pretreatment caused marked reductions in exposure of B6 dams and embryos to both caffeine and TP. Exposure to TB and PX was less consistently affected, although it was reduced by pretreatment with 80 mg beta NF/kg. In contrast, exposure of AKR dams and embryos to caffeine and its metabolites was only slightly affected by beta NF pretreatment. The prevalence of paw malformations in the offspring of treated mice correlated well with effective exposure to both caffeine and TP, but not at all with the administered caffeine dose.

Several studies have linked hepatic metallothionein (MT) synthesis to changes in zinc metabolism in response to various forms of stress and to administration of glucocorticoid hormones. There is also some evidence that the intestinal absorption of Zn is enhanced under such conditions. The present studies were designed to investigate the effect of dexamethasone on the kinetics of Zn uptake in an isolated segment of the adult rat jejunum, perfused through the lumen and maintained in situ. Dexamethasone administered to adrenalectomized rats was found to affect significantly one of the parameters of the equation describing 65Zn uptake. Because the observed effect was kinetically consistent with an increased synthesis of MT in the jejunal mucosa, the synthesis of MT was monitored with 35S-cystine in both the liver and intestine of adrenalectomized rats given dexamethasone. Under these conditions, MT synthesis was significantly increased in the liver but not in the jejunal mucosa. The results indicate that dexamethasone is able to alter the kinetics of Zn uptake in the jejunum, but does so without increased jejunal MT synthesis.

The pharmacokinetics of co-trimoxazole (sulphamethoxazole plus trimethoprim) were studied in end-stage renal disease in patients undergoing treatment with continuous ambulatory peritoneal dialysis (CAPD) and free of peritonitis. Plasma and dialysate concentrations were monitored for 1 exchange after administration of a single oral or intraperitoneal dose of co-trimoxazole, and were fitted by a pharmacokinetic model that took into account the equilibrium nature of CAPD by including return from the peritoneum in oral studies and from the plasma in intraperitoneal studies. Clearances were calculated and compared by analysis of variance. There was a significant effect of direction of flow (p less than 0.01), plasma-peritoneal clearances being larger than peritoneal-plasma clearances for both drugs. In addition, there was a significant difference (p less than 0.0001) between sulphamethoxazole clearances and trimethoprim clearances, with the latter being greater in both directions.

Outbred Swiss Cox mice of both sexes were given single ip injections of 0.5--2.0 mg urethan/g body weight. Lung adenomas began to grow about 7 days after urethan administration. The relationship of plateau tumor level to dose was slightly concave upward. However, the relationship of average tumor number per 10(6) surviving target cells or alveolar type II cells to dose was markedly concave upward. Thus the definition of the urethan dose-lung adenoma prevalence curve should take into account the urethan cytotoxicity. Tumor diameters followed a log normal distribution pattern. The rate of change of geometric mean tumor diameter was independent of sex and urethan dose. In another experiment Swiss Cox mice received ip injections of 1.5 mg urethan/g body weight, and 4 weeks later chronic exposure to urethan in the drinking water was begun. The growth rate of adenomas induced by the single urethan injection was unaffected by subsequent chronic-urethan administration. The results support the common assumption that tumor growth rate is independent of the rate of chronic administration of a carcinogen.

Data from several investigators suggest that the prevalence of urethane-induced lung adenomas in the mouse is more nearly linearly related to the square of the urethane dose than to the dose itself. However, the relationship between urethane dose and integrated internal exposure to urethane has not been established. Outbred male Swiss mice between 41 and 45 days old were injected ip with one of seven doses of urethane ranging from 0.4 to 1.8 mg/g. The rate of elimination of urethane from the blood was followed by assaying the ethanol liberated from urethane by alkaline hydrolysis. The results indicated that urethane elimination is saturable, and saturated at all doses used, with a Vmax of 0.087 mg/ml/hr. Thus, internal exposure to urethane, measured as the area under the blood concentration, time curve, is not linearly related to urethane dose. In the range of doses used in this study, the area under the curve is C0(2)/2Vmax or (D/VD)2 (1/2Vmax), where C0 is the initial concentration; D, the dose; and VD, the volume of distribution. This relationship can be used to predict internal exposure to urethane as a function of dose.

A number of investigators have observed a quadratic relationship between acute urethane dose and cumulative pulmonary adenoma incidence in mice. The hypothesis was tested that this dose-effect relationship may be explained by consideration of the elimination kinetics of urethane. Single doses of 0.4 to 1.8 mg urethane per g body weight were given ip to 6-week-old Swiss-Cox mice. The measure of internal exposure to the intact urethane molecule for a given external urethane dose was taken to be the area under the curve (AUC alpha) of a blood urethane concentration versus time plot. AUC alpha was linearly related to tumor prevalence. When urethane elimination was induced by pretreatment of the mice with p,p'-DDT, the linear relationship of AUC alpha to tumor prevalence was shifted. Reduction of tumor prevalence by p,p'-DDT pretreatment was more marked than that predicted on the basis of exposure to urethane. Thus, the kinetic evidence is consistent with biochemical evidence from other investigators supporting the premise that activation of urethane to a reactive metabolite is required for adenoma formation in the mouse lung. While exposure to the adenogenic moiety is evidently closely proportional to internal exposure to urethane in both pretreated and non-pretreated mice, p,p'-DDT pretreatment causes a shift in this proportionality.

Lead nephropathy, characterized functionally by depression of effective renal plasma flow (ERPF), glomerular filtration rate (GFR), and maximum glucose reabsorption rate, is associated with prolonged occupational exposure to lead. Production of comparable lead-related renal functional deficits in rats has been difficult to achieve. We have examined in rats some of the factors that might be expected to influence the development of lead-induced renal functional damage, using GFR (as inulin clearance), ERPF (as para-aminohippurate clearance), and maximum glucose reabsorption rate as indices of renal functional competence. Although lead produces a significant weight loss, this can be accounted for by reduced food intake and is not associated with reduction in renal function. Even exposure to large amounts of lead in conjunction with other factors, such as controlled diet (NIH-07 and AIN-76) and early age of initial exposure, that might have been expected to increase the rats' susceptibility has not resulted in the development of renal functional deficits. It is unlikely that the rat can be successfully exploited as an animal model of human lead nephropathy with accompanying functional deficits.

Outbred Swiss Cox mice of both sexes were chronically exposed to urethan added to their drinking water at levels of 0.02--0.10% by weight. The number and sizes of lung adenomas that developed as a result were monitored as functions of time and dose rate (DR). The relationship between dose per unit time, or DR, and time (t1) needed for the development of a mean of one observable tumor per mouse was: DR x tn1 = k, where K and n are constants. The value of n was 2.75. This value could be largely accounted for by the DR-independent tumor growth time, although an increase in the number of target cells at higher urethan dose rates may also be a factor in the relationship between DR and t1. Examination of the relationships between cumulative incidence and DR and between cumulative incidence and adenoma induction time suggests that urethan acts at one stage of a two-stage mechanism in the induction of mouse lung adenomas.

Twelve patients with haematological malignancy received cyclophosphamide 120 mg/kg, fractionated total body irradiation 12 Gy, oral cyclosporin and an HLA-identical sibling marrow transplant depleted of T cells by incubation with monoclonal antibodies directed against the CD2 and CD8 antigens and rabbit complement. The phenotype of the residual T cells in the donor marrow inocula was CD3+, CD4+, CD8-. To exclude the possibility that this represented modulation or blocking of the CD8 antigen, T-depleted and non-depleted marrow aliquots from these donors were bulk-cultured for 10 days with phytohaemagglutinin and interleukin-2. Even after this attempted expansion, only a small proportion of cultured T cells from the depleted aliquots (in contrast to the non-depleted aliquots) expressed the CD8 antigen. Since all patients receiving CD3+, CD4+, CD8- marrow developed mild or moderate acute graft-versus-host disease (GVHD), we conclude that CD4+ T cells are capable of initiating acute GVHD across non-MHC barriers in man.

This study was performed to determine the effect of coadministered oral metoclopramide on the absorption of oral cyclosporine in 14 kidney transplant patients with stable renal function. The study was conducted on two consecutive days. Ten patients were studied twice and four patients once, giving 24 studies. The total dosage of metoclopramide was 20 mg. The day on which metoclopramide was administered was chosen randomly. Whole blood cyclosporine levels were analyzed by high performance liquid chromatography. Coadministration of cyclosporine with metoclopramide resulted in a significant increase in mean maximum blood concentration (567 ng/mL nu 388 ng/mL) and mean area under the blood concentration nu time curve (4120 ng X h/mL nu 3370 ng X h/mL), and a significant decrease in mean time to reach maximum concentration: The mean increase in area under the blood concentration versus time curve was 29%. No significant changes were observed in the elimination of cyclosporine when it was coadministered with metoclopramide. These observations suggest that coadministered metoclopramide increased the total absorption of cyclosporine. Metoclopramide has been shown to hasten gastric emptying; since cyclosporine is absorbed predominantly in the small intestine, coadministration of metoclopramide resulted in increased bioavailability of cyclosporine.

Acetazolamide, an inhibitor of the enzyme carbonic anhydrase (E.C. 4.2.1.1.), causes a unique congenital anomaly characterized by postaxial reduction of the distal portion of the right forelimb. To gain an understanding of the mechanism of teratogenesis, the activity of carbonic anhydrase in sensitive and resistant mouse strains, and its inhibition by acetazolamide, were examined. Differences in teratologic sensitivity were found not to be attributable to differences in maternal or embryonic drug levels. Enzyme inhibition at acetazolamide concentrations ranging between 10(-11) and 10(-5) M did not differ between the mouse strains when adult erythrocytes or day 12 embryos were assayed. However, in day 10 embryos, the period of maximum teratologic susceptibility, a small strain difference was found which suggested that the form of carbonic anhydrase in the susceptible CBA/J strain at this time is somewhat more sensitive to inhibition by acetazolamide than the form found in the resistant SWV strain. The results suggest further that more than one isozyme of carbonic anhydrase may be present in all three samples.

Under the Occupational Safety and Health Administration (OSHA) standard for occupational exposure to lead, workers whose blood lead concentration has reached or exceeded a specified trigger level are removed from work areas where 8-hr time-weighted-average air lead concentration is equal to or in excess of a specified value, and are returned when two consecutive blood lead concentration measurements have been at or below the return trigger level. Initial removal and return triggers, of 80 and 60 micrograms/100 g respectively, instituted in 1979, were supplanted in a scheduled sequence by 70/50 and later by 60/40 triggers. This paper presents a descriptive summary of lead industry-wide experience with medical removals from high workplace-lead exposure as mandated by OSHA, and an examination of the influence of job tenure on length of removal. Median length of removal under the 80/60 triggers was 3.4 months; under the 70/50 triggers, it was 4.4 months. Median length of removal under the 60/40 triggers can only be estimated due to censoring of the data set, but was between 6 and 8 months for employees removed during the first 4 months after institution of the 60/40 triggers. Respirator use and company identity significantly influenced length of removal only under the 80/60 triggers. Job tenure did not influence length of removal of employees removed and returned within the 18-month limit. However, mean tenure of employees reaching 18 months on removal was significantly longer than mean tenure of employees removed and returned within 18 months, under all three sets of triggers.(ABSTRACT TRUNCATED AT 250 WORDS)

A model of the growing small animal skeleton has been developed. The model accurately reproduces a variety of different kinds of measurements made at different ages in different species, as well as reproducing a precise and detailed series of measurements in the growing guinea pig. Of the multiple mechanisms responsible for transfer of bone-seeking elements from blood to bone and back again, several are quantitatively insignificant on a skeletal scale. Surface (rapid) exchange, diffuse (slow) exchange, and secretion of new bone during growth are the principal determinants of skeletal metabolism. Bone blood flow can probably by satisfactorily modeled as a combination of a basal flow rate plus an increment that is directly proportional to formation rate of new bone.

The relationship among dose, metabolism and hepatotoxicity in mice which resulted from subchronic exposure to the chlorinated solvents trichloroethylene (TRI) and perchloroethylene (PER) were examined. Male Swiss-Cox mice received either TRI (0 to 3200 mg/kg/day) of PER (0 to 2000 mg/kg/day) in corn oil by gavage for 6 weeks. Urinary metabolites from individual mice were quantified to estimate the extent to which each compound was metabolized. Four parameters of hepatotoxicity were assessed: liver weight, triglycerides, glucose-6-phosphatase (G6P) activity, and SGPT activity. TRI significantly affected liver weight and G6P activity; PER affected all four parameters. The metabolism of TRI was linearly related to dose through 1600 mg/kg, but then became saturated. The metabolism of PER was saturable. The dose-effect curves of the affected hepatotoxicity parameters of both compounds were nonlinear and resembled the dose-metabolism graph of the corresponding solvent. Plots of the hepatotoxicity data of each compound against total urinary metabolites were linear in all cases, suggesting that the hepatotoxicity of both PER and TRI in mice is directly related to the extent of their metabolism. This pattern is consistent with formation of the toxic intermediate in the primary metabolic pathway of each compound.

Renal mechanisms for handling delta-aminolevulinic acid (ALA) were investigated in control and lead-exposed rats infused with ALA at a range of rates which produced plasma ALA as high as 2380 ng/mL. The presence of both reabsorption and secretion mechanisms was demonstrated. Reabsorption is the more efficient of the two mechanisms at low plasma ALA concentrations, and masks secretion in this range. Net secretion is observed at very high plasma ALA concentrations. Exposure to up to 2000 micrograms lead/mL of drinking water for 12 to 18 months had no measurable effect on net ALA excretion at a given plasma ALA level.

The expected relationship between the apparent half-life of blood lead (PbB) and the length of previous exposure is compared with the observed relationship in a group of workers on strike from a primary smelter where they had been employed for from a few months to ten years. Within this group, the apparent PbB half-life was positively correlated both with pre-strike PbB and with length of exposure to lead. It is likely that the dependence of apparent half-life on pre-strike PbB is primarily a reflection of interindividual differences in lead kinetics in these men. The direct dependence of apparent half-life on duration of lead exposure is consistent with published data from former lead workers and from human subjects experimentally exposed to lead.

Sixteen patients with haematological malignancy received high-dose chemotherapy or chemotherapy and total body irradiation followed by an HLA-identical sibling marrow transplant from which the T lymphocytes had been depleted prior to infusion by incubation with an anti-CD2 anti-T cell antibody with (seven patients) or without (nine patients) an anti-CD8 anti-T cell antibody together with rabbit complement. Additionally, all patients received cyclosporin. The number of T cells present in the donor marrow was determined by limiting dilution analysis, and was found to correlate with the subsequent incidence and severity of acute graft-versus-host disease (GVHD). The number of T cells infused into patients with no acute GVHD or with minimal acute GVHD of the skin (skin rash present for 14 days or less) was 1.3 +/- 1.0 x 10(5)/kg, while the number infused into those with moderate acute GVHD or with skin acute GVHD present for 15 days or more was 12.3 +/- 11.5 x 10(5)/kg (p less than 0.001). Thus a dose of 10(5) (or less) T cells/kg was associated with minimal or no acute GVHD, while 10(6) T cells/kg (or more) caused significant disease.

Net free fatty acid release from adipose tissue taken from male rats fed a stock diet unsupplemented with chromium was significantly greater than that from adipose tissue taken from chromium-supplemented rats. This enhanced net lipolysis was unaccompanied by any evidence of a compensatory increase in reesterification. Specifically, the glycerokinase-catalyzed direct phosphorylation of glycerol, which might have provided an alternate supply of alpha-glycerophosphate for reesterification in the absence of glycolytic production of alpha-glycerophosphate, was significantly reduced. These animals also showed an abnormal glucose tolerance response. In contrast, male rats fed a purified diet unsupplemented with chromium appeared to be marginally chromium-deficient as judged by a glucose tolerance test but did not show any alterations in adipose tissue metabolism attributable to the adequacy of chromium nutriture.

Kinetic interactions among chemicals present in a mixture can influence the relationship between administered and delivered or effective dose; these interactions are distinct from dynamic interactions such as, for example, competition between two chemicals for receptor binding sites. The relationship between administered and effective dose depends on a number of biochemical, physiological, and physical factors such as age, sex, level of physical activity, route of administration, dose pattern, and bioavailability. In addition, interactions among chemicals may limit or increase the effective dose relative to the administered dose for any of the chemicals of a mixture. If the mechanism of the interaction is known, the direction and general magnitude of its effects may be predictable. A variety of potential interactions is briefly reviewed, and selected illustrations of these interactions are given. Two types of interactions likely to be pervasive in mixtures of chemically related bioactive materials are considered in greater detail. These interactions are induction of metabolizing enzymes such as the mixed-function oxidases, and competition of structurally similar chemicals for active sites on metabolizing enzymes. Simulations are presented to illustrate the consequences of these interactions, and examples of their occurrence are given.