Biomedical subjects

C A Franklin

Publications and source records attributed to C A Franklin.

At least 19 recordsLinked to original sources

PubMed1998

Evaluation and modification of a physiologically based model of lead kinetics using data from a sequential isotope study in cynomolgus monkeys.

Endogenous (predominantly bone) and exogenous lead were differentially labeled in two 11-year-old female cynomolgus monkeys (Macaca fascicularis) to establish the contributions of the two sources to blood lead. The monkeys had been administered a common lead isotope "mix" at the rate of about 1300 micrograms Pb/kg body wt/day from age 10 months until the start of the study. On day 0, common lead was replaced in sequence by mixes artificially enriched in 204Pb, 206Pb, and 207Pb, given for periods of from 50 to 281 days. Total lead ingestion rate was held constant except during administration of the 207Pb-enriched mix to one of the monkeys, when it was reduced to 650 micrograms/kg/day. Blood and bone were sampled at intervals and analyzed for their content of each of the isotope mixes. A physiologically based model of human lead kinetics was scaled to the cynomolgus monkey and fit to the data to test the correctness of the model structure and to assist with interpretation of study results. Fractional absorption was varied to achieve the best visual fits of the scaled model to blood and bone concentration data for each monkey. The model failed to reproduce the sharp drop in isotope concentrations in blood observed after each exchange of isotope mix. Consequently, it was revised to include a rapid-turnover trabecular bone compartment and a slow-turnover cortical bone compartment, using estimates of trabecular and cortical bone turnover rates from histomorphometric studies in adult cynomolgus monkeys. The revised model fit most of the sets of bone and blood concentrations well. About 17% of the blood lead originated from bone after 11 years of exposure, at blood lead concentrations in excess of 50 micrograms/dl. The rate of return of common lead from bone, as estimated from the model, was 28 micrograms/day just before termination of controlled common lead exposure on day 0. Based on the success of the scaled human model in fitting these data and on the absolute and relative values of bone and blood lead concentrations, the metabolism of lead in the cynomolgus monkey appears to be similar to human lead metabolism.

Americium↗

PubMed1997

Use of sequentially administered stable lead isotopes to investigate changes in blood lead during pregnancy in a nonhuman primate (Macaca fascicularis).

The effects of pregnancy on the flux of lead from maternal bone were investigated in five females from a unique colony of cynomolgus monkeys (Macaca fascicularis) which had been dosed orally with lead (approximately 1100-1300 microg Pb/kg body wt) throughout their lives (about 14 years). Through the use of stable lead isotopes 204Pb, 206Pb, and 207Pb, it was possible to differentiate between the lead contributed to blood lead from the skeleton and the lead contributed from the current oral dose. Blood samples and bone biopsy samples taken before, during, and after pregnancy were analyzed for lead (total and stable isotope ratios) by thermal ionization mass spectrometry. Through the use of end-member unmixing equations, the contribution to blood of lead from maternal bone during pregnancy was estimated and compared to the contribution of lead from maternal bone before pregnancy. A 29 to 56% decrease in bone lead mobilization in the first trimester was followed by an increase in the second and third trimesters, up to 44% over baseline levels. In one monkey, the third-trimester increase did not reach baseline levels. In a single low-lead monkey, a similar decrease in the first trimester was followed by a 60% increase in the third trimester, indicating that a similar pattern of flux is seen over a wide range of lead concentrations. Analysis of maternal bone and fetal bone, brain, liver, and kidneys confirmed a substantial transplacental transfer of endogenous lead. Lead concentrations in fetal bone often exceeded maternal bone lead concentrations. From 7 to 39% of the lead in the fetal skeleton originated from the maternal skeleton.

Administration, Oral↗

PubMed1996

Measurement of the flux of lead from bone to blood in a nonhuman primate (Macaca fascicularis) by sequential administration of stable lead isotopes.

To better understand the kinetics of the transfer of lead from bone to blood, we have developed and tested a method in which sequential doses of lead, each enriched with a different stable isotope, were administered in a nonhuman primate Macaca fascicularis whose skeleton had been previously labeled with lead of known isotopic composition. Lead isotopic ratios of blood and bone samples, analyzed by thermal ionization mass spectrometry (TIMS), were unmixed by isotope dilution techniques. The first label administered allows the contribution from historical bone stores to be measured. Subsequent labels allow measurement of both the historical bone stores and the previous labels that have become recently incorporated into bone. The method may be extended to studies of bone lead mobilization in pregnancy, lactation, menopause, or in disease states such as postmenopausal osteoporosis.

Animals↗

PubMed1996

Plasma and blood lead concentrations, lead absorption, and lead excretion in nonhuman primates.

In order to assess the comparability of lead disposition in the cynomolgus monkey to that in the human, we determined the relationships among blood lead concentration, plasma lead concentration, and lead excretion in monkeys. Six adult (3-5 kg) female cynomolgus monkeys (Macaca fascicularis) without previous experimental lead exposure were given single intravenous injections of from 750 to 3300 micrograms lead as lead nitrate, labeled with 210Pb, per kilogram body weight. Four additional monkeys, fasted overnight, were administered single oral doses of either 750 or 1500 micrograms lead as lead nitrate, labeled with 210 Pb, per kilogram for the assessment of fractional absorption. Blood and plasma lead concentrations (10 monkeys) and urinary and fecal excretion of lead (2 monkeys) were followed up for up to 16 days after lead administration. Fractional absorption from an oral dose was 44% at the lower of the two doses and 22-28% at the higher dose. The relationship between plasma and blood lead concentrations was found to be similar to that in humans, with plasma lead concentration at most a few percent of total blood lead concentration at low concentrations. Partitioning of lead across the red cell membrane in the 2 monkeys given exceptionally high doses (3300 micrograms/kg) intravenously was distinctly lower than that in the 4 monkeys given lower intravenous doses. Urinary clearance of lead in these 2 monkeys was 19% of the estimated glomerular filtration rate, within the range of efficiencies reported for humans. Fecal clearance, however, was anomalous and appeared to be an artifact of the very high dose. Examination of published data for urinary and fecal lead excretion in three adult baboons showed that both functions in the baboons were quantitatively similar to those in humans. Urinary clearance in the baboons was 14-24% of the estimated glomerular filtration rate, and fecal clearance was 78-85% of the urinary clearance. We conclude that nonhuman and human primates are comparable with respect to the relationship of plasma lead concentration to blood lead concentration and the relative efficiency of lead excretion in urine and feces.

Absorption↗

PubMed1994

Air pollution and childhood respiratory health: exposure to sulfate and ozone in 10 Canadian rural communities.

This study was designed to examine differences in the respiratory health status of preadolescent school children, aged 7-11 years, who resided in 10 rural Canadian communities areas of moderate and low exposure to regional sulfate and ozone pollution. Five of the communities were located in central Saskatchewan, a low-exposure region, and five were located in southwestern Ontario, an area with moderately elevated exposures resulting from long-range atmospheric transport of polluted air masses. In this cross-sectional study, the child's respiratory symptoms and illness history were evaluated using a parent-completed questionnaire, administered in September 1985. Respiratory function was assessed once for each child in the schools between October 1985 and March 1986, by the measurement of pulmonary function for forced vital capacity (FVC), forced expiratory volume in 1 sec (FEV1.0), peak expiratory flow rate (PEFR), mean forced expiratory flow rate during the middle half of the FVC curve (FEF25-75), and maximal expiratory flow at 50% of the expired vital capacity (V50max). The 1986 annual mean of the 1-hr daily maxima of ozone was higher in Ontario (46.3 ppb) than in Saskatchewan (34.1 ppb), with 90th percentile concentrations of 80 ppb in Ontario and 47 ppb in Saskatchewan. Summertime 1-hr daily maxima means were 69.0 ppb in Ontario and 36.1 ppb in Saskatchewan. Annual mean and 90th percentile concentrations of inhalable sulfates were three times higher in Ontario than in Saskatchewan; there were no significant differences in levels of inhalable particles (PM10) or particulate nitrates. Levels of sulfur dioxide (SO2) and nitrogen dioxide (NO2) were low in both regions. After controlling for the effects of age, sex, parental smoking, parental education, and gas cooking, no significant regional differences were observed in rates of chronic cough or phlegm, persistent wheeze, current asthma, bronchitis in the past year, or any chest illness that kept the child at home for 3 or more consecutive days during the previous year. Children living in southwestern Ontario had statistically significant (P < 0.01) mean decrements of 1.7% in FVC and 1.3% in FEV1.0 compared with Saskatchewan children, after adjusting for age, sex, weight, standing height, parental smoking, and gas cooking. There were no statistically significant regional differences in the pulmonary flow parameters (P > 0.05).

Air Pollutants↗

PubMed1992

Percutaneous absorption and metabolism of pyrene, benzo[a]pyrene, and di(2-ethylhexyl) phthalate: comparison of in vitro and in vivo results in the hairless guinea pig.

The in vitro and in vivo absorption and metabolism of pyrene, benzo[a]pyrene, and di(2-ethylhexyl) phthalate (DEHP) were investigated in the hairless guinea pig. The in vitro method, which involved the use of flow-through diffusion cells and Hepes-buffered Hanks' balanced salt solution containing 4% bovine serum albumin as perfusate, was demonstrated to be a suitable system for predicting in vivo absorption of the above lipophilic compounds. The successful application of the in vitro technique for these compounds is significant because no satisfactory in vitro method has hitherto been developed to predict in vivo absorption of highly lipophilic chemicals. Quantification of parent compounds and metabolites that permeated into perfusates and those that remained in skin discs provided insight into the process by which the chemicals penetrated through the skin. Pyrene was absorbed primarily by a passive diffusion process, although a small fraction of the administered dose was biotransformed into metabolites in the skin and partitioned into the receptor fluid. Absorption of benzo[a]pyrene was mediated by biotransformation processes. A metabolite derived from the ultimate carcinogen of this compound, benzo[a]pyrene r-7, t-8,9,10-tetrahydrotetrol, was identified in the receptor fluid. Most of the administered DEHP remained in the skin and only a very small fraction of the dose partitioned into the receptor fluid in either viable or nonviable skin. Data from the present study led to the conclusion that the in vitro method can be utilized to predict in vivo absorption for compounds of high lipophilicity and that dermal metabolism facilitates partitioning of metabolites into the receptor fluid and hence may affect the biological activities of dermally applied compounds.

Administration, Cutaneous↗

PubMed1992

Neuropathologic findings in young male rats in a subchronic oral toxicity study using triethyl lead.

This study was undertaken to ascertain the neuropathologic effects of low level exposure of triethyl lead (3EL) to young male rats. Groups of 20 male Sprague-Dawley weanling rats were given 3EL at 0, 0.05, 0.10, 0.20, 0.50, and 1.00 mg/kg body wt for 91 days, 5 days/week by oral gavage. Lead acetate (PbHOAC) was given at 200 mg/kg body wt/day as a positive control. Animals (five or six) were perfused with glutaraldehyde following barbiturate anesthesia at the termination of the experiment. These animals and the remaining members of the group received a thorough gross and microscopic postmortem examination. Sections of the central, peripheral, and autonomic nervous systems were examined and lesions scored. No lesions were noted in the brain, but randomly distributed light microscopic changes of spinal cord Wallerian degeneration were noted to increase in a dose responsive manner (rho = 0.48; p < 0.01), with 3EL administration. Ultrastructural examination of selected sections of the lumbosacral nerves, revealed lesions characterized by reduced neurofilaments and neurotubules, and irregular lamellated axoplasmic dense bodies in all animals receiving lead. Organolead was only detected in animals receiving 3EL, but lead cations were detected in all lead-treated animals. The brain lead levels of 1.00 mg/kg/day and 200 mg Pb acetate positive control animals were equivalent. As distinctive ultrastructural lesions were seen in all rats treated with 3EL, we suggest that the no observed adverse effect level (NOAEL) for 3EL be lowered to less than 0.05 mg/kg/day.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

Sampling of cortical and trabecular bone for lead analysis: method development in a study of lead mobilization during pregnancy.

The paper describes a methodological approach to the investigation of maternal-fetal transfer of lead in a non-human primate species, with particular focus on skeletal tissue, which is known to be a site of lead deposition. Eight female cynomolgus monkeys were dosed with lead acetate during gestation, and in four of the animals, the isotopic composition of the lead was modified by enriching the amount of the stable isotope 204Pb included in the dose. Biopsy and dissection procedures for the preparation of bone samples for lead analysis and stable lead isotope analysis are described. Emphasis is placed on the containment of potential contamination of the samples by lead during preparation. Containment procedures included: use of a Class 100 clean room, special cleaning regimes and use of Teflon containers and stainless steel instruments. Preliminary data of lead concentrations in adult bone (trabecular and cortical) and fetal bone subsequent to the dosing regimen of lead during pregnancy, suggest notable differences between the two bone "compartments" examined. The bone samples of fetuses from the dams which had received enriched 204Pb showed drastically reduced 206Pb/204Pb isotope ratios.

Animals↗

PubMed1991

Respiratory health effects of home dampness and molds among Canadian children.

In 1988, the authors conducted a questionnaire-based study on the health effects of the indoor environment in 30 Canadian communities. This paper focuses on the association between the respiratory health of young children and home dampness and molds. A total of 17,962 parents or guardians of schoolchildren received a questionnaire, and 14,948 (83.2%) questionnaires were returned. Children living in mobile homes, tents, and boats were excluded as were those with cystic fibrosis, leaving 13,495 children included in the study group. The housing stock was distributed as follows: 81% were one-family detached homes, 6% were one-family attached homes, and 13% were buildings for two or more families. Molds were reported in 32.4%, flooding in 24.1%, and moisture in 14.1% of the homes. Prevalences of all respiratory symptoms were consistently higher in homes with reported molds or dampness; i.e., adjusted odds ratios ranged from 1.32 (95% confidence interval 1.06-1.39) for bronchitis to 1.89 (95% confidence interval 1.58-2.26) for cough. The prevalence of home dampness or molds, 37.8%, indicates that it is an important public health issue. Further studies are required to elucidate the pathogenesis.

Canada↗

PubMed1991

Percutaneous absorption/metabolism of phenanthrene in the hairless guinea pig: comparison of in vitro and in vivo results.

The in vitro and in vivo percutaneous absorption/metabolism of phenanthrene was investigated in hairless guinea pigs. Flow-through diffusion cells and Hepes-buffered Hanks' balanced salt solution (HHBSS) as receptor fluid were used in the in vitro system. When phenanthrene was applied to excised guinea pig skin mounted on the cells at dose levels of 6.6 and 15.2 micrograms/cm2, 89.7 and 79.1% of the administered doses were respectively absorbed into the skin and receptor fluids during a 24-hr perfusion period. These results are consistent with the in vivo data which showed approximately 80% absorption over the same period of time. Phenanthrene was metabolized in vitro into phenanthrene 9,10-dihydrodiol, 3,4-dihydrodiol, 1,2-dihydrodiol, and traces of hydroxy phenanthrenes. Of the materials absorbed in vitro, 92% was the parent compound and 7% the dihydrodiol metabolites. When a nonviable in vitro system was used, 68% of the applied 15.2 micrograms/cm2 dose was absorbed. Data from the present study demonstrate that the in vitro system is a good model for predicting in vivo percutaneous absorption of phenanthrene, and that penetration of phenanthrene through the skin is controlled more by the passive rate of diffusion than by metabolism.

Animals↗

PubMed1990

Subchronic oral toxicity of triethyl lead in the male weanling rat. Clinical, biochemical, hematological, and histopathological effects.

This study was designed to ascertain the effects of low level exposure of triethyl lead (3EL) to the male weanling rat. Groups of 20 animals were administered by gavage 3EL at 0.05, 0.10, 0.20, 0.50, and 1.00 mg/kg body wt for 91 days, 5 days/week. Lead acetate (PbHOAC) at 200 mg/kg body wt/day was given as a positive control. Weight gain was reduced in those animals receiving 1.0 3EL. Spleen and kidney weights were elevated in the PbHOAC group. Residues of 3EL and its metabolites diethyl lead (2EL) and lead (Pb) accumulated in a dose-dependent manner in blood, liver, kidney, and brain; 3EL accumulated preferentially in the liver while inorganic lead accumulated in the kidney. Dose-dependent changes occurred in serum calcium which was decreased and in phosphorus which was elevated for all dose groups. Serum cholesterol was elevated in the three highest 3EL groups as was alkaline phosphatase. LDH was lowered in the PbHOAC-treated group but microsomal aniline hydroxylase was elevated. Hematological changes consisted of elevated platelet counts in the 1.0 3EL group and decreased mean corpuscular hemoglobin content and mean corpuscular volume in the PbHOAC-treated group. Treatment related histopathological changes were seen in thyroid, liver, kidney, and bone marrow. Based on these data a no observed adverse effect level for 3EL was set at 0.10 mg/kg/body wt.

Administration, Oral↗

PubMed1990

Strategies for testing the "irritation-signaling" model for chronic lung effects of fine acid particles.

The "irritation signaling" model proposed that a long term contribution to chronic bronchitis might result from the repeated delivery of "signals" resulting from temporary localized acidification of the bronchial epithelium by the action of individual particles. This led to a prediction that the effectiveness of particles in inducing changes in mucus secreting cell numbers/types should depend on the number of particles deposited that contained a particular amount of acid--implying that particles below a certain size cutoff (and therefore lacking a minimum amount of acid) should be ineffective; and that particle potency per unit weight should be greatest at the cutoff and decline strongly above the cutoff. Since the development of this hypothesis both epidemiological observations and some experimental studies have tended to reinforce the notion that acid particles can make a contribution to relatively long lasting bronchitic-like changes, and enhance the desirability of more direct testing of the model. In this paper we develop a general theoretical framework for the contributions of environmental agents to chronic obstructive lung disease, and a series of alternative hypotheses against which the predictions of the "irritant signaling" model can be compared. Based on this, we suggest a research program that could be used to further develop and test the model and reasonable alternatives.

Acids↗

PubMed1990

Dermal absorption of the phenoxy herbicides 2,4-D, 2,4-D amine, 2,4-D isooctyl, and 2,4,5-T in rabbits, rats, rhesus monkeys, and humans: a cross-species comparison.

Dermal absorption of the 14C-ring-labeled phenoxy herbicides 2,4-D [(2,4-dichlorophenoxy)acetic acid], 2,4-D amine (2,4-dichlorophenoxyacetic acid dimethylamine), 2,4-D isooctyl (2,4-dichlorophenoxyacetic acid isooctyl ester), and 2,4,5-T amine (2,4,5-trichlorophenoxyacetic acid trimethylamine) was examined following topical applications of the herbicides to the back of rabbits, the back and tail of rats, the forearm and forehead of rhesus monkeys, and the forehead of human volunteers. The effect of three pesticide vehicles (water, acetone, and Esteron LV96) was also investigated. The total percent dermal absorption was calculated from the mean percent urinary recoveries from the animal tests and corrected for nonurinary excretion of the radiolabel using data from intramuscular (im) injections. The human data are reported without im correction. The reliability of animal data for modelling human dermal absorption of pesticides is highlighted.

2,4,5-Trichlorophenoxyacetic Acid↗

PubMed1989

Respiratory health effects associated with ambient sulfates and ozone in two rural Canadian communities.

A cross-sectional epidemiological study investigating the respiratory health of children in two Canadian communities was conducted in 1983-1984 in Tillsonburg, Ontario, located in a region of moderately elevated concentrations of transported air pollutants, and in Portage la Prairie, Manitoba, situated in a low pollution area. There were no significant local sources of industrial emissions in either community. Seven hundred and thirty-five children aged 7-12 were studied in the first town and 895 in the second. Respiratory health was assessed by the measurement of the forced vital capacity (FVC) and forced expiratory volume in 1 sec (FEV1.0) of each child, and by evaluation of the child's respiratory symptoms and illnesses using a parent-completed questionnaire. Sulfur dioxide (SO2), sulfate, and particulate nitrate levels were significantly higher in Tillsonburg than in Portage la Prairie (P less than 0.05), but nitrogen dioxide (NO2) and inhalable particles (PM10) differed little between the communities. Historical data in the vicinity of Tillsonburg indicated that average annual levels of sulfates, total nitrates, and ozone (O3) did not vary markedly in the 9-year period preceding the study. The results show that Tillsonburg children had statistically significant (P less than 0.001) lower levels of 2% for FVC and 1.7% for FEV1.0 as compared with children in Portage la Prairie. These differences could not be explained by parental smoking or education, the use of gas cooking or wood heating fuels, pollution levels on the day of testing, or differences in age, sex, height, or weight. The differences persisted when children with cough with phlegm, asthma, wheeze, inhalant allergies, or hospitalization before age 2 for a chest illness were excluded from analysis. With the exception of inhalant allergies, which occurred more frequently in Tillsonburg children, the prevalence of chronic respiratory symptoms and illnesses was similar in the two communities.

Air Pollutants↗

PubMed1989

Acute lung function responses to ambient acid aerosol exposures in children.

We examined the relationship between lung function changes and ambient acid aerosol episodes in children attending a residential summer camp. Young females (112) performed daily spirometry, and 96 were assessed on one occasion for airway hyperresponsiveness using a methacholine bronchoprovocation test. Air quality measurements were performed on site and four distinct acid aerosol episodes were observed during the 41-day study. The maximum values observed during the 41-day study were: O3 at 143 ppb; H2SO4 at 47.7 micrograms/m3; and [H+] at 550 nmole/m3. Maximum decrements of 3.5 and 7% for FEV1 and PEF, respectively, were observed to be associated with the air pollution episodes. There was some evidence of a differential lung function response to the episodes where children with a positive response to a methacholine challenge had larger decrements compared to their nonresponsive counterparts.

Acid Rain↗

PubMed1989

Exposures to acidic aerosols.

Ambient monitoring of acid aerosols in four U.S. cities and in a rural region of southern Ontario clearly show distinct periods of strong acidity. Measurements made in Kingston, TN, and Steubenville, OH, resulted in 24-hr H+ ion concentrations exceeding 100 nmole/m3 more than 10 times during summer months. Periods of elevated acidic aerosols occur less frequently in winter months. The H+ determined during episodic conditions in southern Ontario indicates that respiratory tract deposition can exceed the effects level reported in clinical studies. Observed 12-hr H+ concentrations exceeded 550 nmole/m3 (approximately 27 micrograms/m3 H2SO4). The maximum estimated 1-hr concentration exceeded 1500 nmole/m3 for H+ ions. At these concentrations, an active child might receive more than 2000 nmole of H+ ion in 12 hr and in excess of 900 nmole during the hour when H2SO4 exceeded 50 micrograms/m3.

Acid Rain↗

PubMed1989

Weight loss and senile dementia in an institutionalized elderly population.

The purpose of this study was to determine whether patients with Alzheimer's disease or senile dementia have a higher incidence of underweight and weight loss than non-demented patients. In a retrospective study, the admission weight and height and the current weight of 36 patients with Alzheimer's disease and senile dementia of the Alzheimer's type were compared with those of 31 non-demented patients. Patients with Alzheimer's disease or senile dementia were significantly (p less than .05) further below minimum acceptable body weight on admission and were significantly (p less than .05) further below minimum acceptable body weight after an average of 17 months in the institution in comparison with the control group. Additional research is needed to determine whether the weight loss seen in patients with Alzheimer's disease or senile dementia is due to a metabolic aberration inherent in the disease or to management issues in feeding those patients.

Aged↗

PubMed1988

Percutaneous absorption of cis- and trans-permethrin in rhesus monkeys and rats: anatomic site and interspecies variation.

Dermal absorption of cis- and trans-permethrin isomers was determined in rhesus monkeys and Sprague-Dawley rats. Four 14C radiolabels were used (cis alcohol, cis cyclopropyl, trans alcohol, and trans cyclopropyl). One microcurie of each radiolabel was applied to either the forehead or forearm of rhesus monkeys or to the midlumbosacral region of the rat. Urine was collected for 7 or 14 d. Correction factors for incomplete urine excretion were derived from measurements of radiolabel in the urine following im injection of an equivalent dose. It was noted that the total im dose recovered in the urine of both species was lower for the cis isomer than for the trans isomer. There was no significant difference between the dermal absorption of the cis isomer and that of the trans isomer in monkeys. The forehead, however, was more permeable for both isomers than the forearm (alcohol- and cyclopropyl-labeled cis and trans isomers, respectively, showed permeation in forehead, cis 28 +/- 6%, 24 +/- 6%, trans 21 +/- 3%, 14 +/- 4%, forearm, cis 9 +/- 3%, 9 +/- 3%, trans 12 +/- 3%, and 5 +/- 2%). There was no difference between absorption of the isomers (cis 46 +/- 4%, trans 43 +/- 5%) in rats, but absorption was significantly greater than in monkeys. The IM urinary t1/2 values in monkeys and rats were similar for both isomers (0.8-1.1 d).

Animals↗