A perspective on In vitro developmental neurotoxicity test assay results: An expert panel review.

For decades, there has been increasing concern about the potential developmental neurotoxicity (DNT) associated with chemicals. Regulatory agencies have historically utilized standardized in vivo testing to evaluate DNT. Owing to considerations including higher-throughput screening for DNT, reduction in animal use, and potential cost efficiencies, the development of alternative new approach methods (NAMs) occurred; specifically, the advent of the DNT in vitro test battery (DNT IVB). SciPinion convened an expert panel to address specific questions related to the interpretation of in vitro DNT test data. The consensus of the expert panel was that the DNT IVB might be used during initial screening, but it is not presently a complete or surrogate approach to determine whether a chemical is a DNT in humans. By itself, the DNT IVB does not have the ability to capture nuances and complexity of the developing nervous system and associated outcomes including behavioral ontogeny, motor activity, sensory function, and learning/memory. Presently, such developmental landmarks cannot be adequately assessed in the DNT IVB or by other NAMs. The expert panel (all who serve as co-authors of this review) recommended that additional data generation and validation is required before the DNT IVB can be considered for application within global regulatory frameworks for decision-making.

Impact of wind speed and air pollution on COVID-19 transmission in Pakistan.

This study investigated the effect of wind speed and air pollution on COVID-19 from March 10, 2020, to October 04, 2020, in Pakistan. Wind speed and COVID-19 had positive correlation in Pakistan and its provinces. The inverted U-shaped dose-response curve was found for wind speed and COVID-19 in Punjab. Initially, the dose-response curve showed a positive link between wind speed and COVID-19 in Pakistan, Sindh, Khyber Pakhtunkhwa, and Islamabad Capital Territory. Later, it becomes downward sloped in Sindh, Khyber Pakhtunkhwa, and Islamabad Capital Territory. The expected log count of COVID-19 was increased by 0.113 times (Pakistan), 0.074 times (Punjab), 0.042 times (Sindh), and 0.082 times (Khyber Pakhtunkhwa) for a 1 km/h increase in the wind speed. The correlation between particulate matter and COVID-19 was positive (Pakistan, Punjab, and Islamabad Capital Territory) and negative (Sindh). The dose-response curve for particulate matter and COVID-19 had inverted U-shaped (Pakistan, Punjab, and Khyber Pakhtunkhwa) positively sloped (Islamabad Capital Territory), and negatively sloped (Sindh). The inverted U-shaped association shows that the COVID-19 initially increased due to a rise in the particulate matter but reduced when the particulate matter was above the threshold level. The particulate matter was also responsible to wear face masks and restricted mobility. The expected log count of COVID-19 cases was reduced by 0.005 times in Sindh for 1 unit increase in particulate matter. It is recommended to reduce particulate matter to control respiratory problems. The government should use media (print, electronic, social) and educational syllabus to create awareness about precautionary measures.

Obesity among adolescents in five Arab countries; relative to gender and age / La obesidad entre los adolescentes en cinco países árabes; en relación con el género y la edad

Objective: To determine the prevalence of overweight and obesity among adolescents in five Arab countries, relative to age and sex. Methods: A multistage stratified random sampling technique was used to select the secondary school students from five Arab countries (Kuwait, Libya, Palestine, Syria and United Arab Emirates). The total sample was 3302 (1584 males, 1718 females). Weight and height were measured, and body mass index was used to calculate the proportion of overweight and obesity based on the International Obesity Task Force standard (IOTF). Results: Kuwaiti adolescents showed the highest prevalence of overweight and obesity among both males and females, compared to their counterparts in other countries. There was no trend in the proportion of overweight and obesity by age in any of the countries included in the study. Conclusion: Adolescent obesity has reached a critical level in the Arab countries. Therefore there is an urgent need to establish programs to prevent and control obesity among schoolchildren in these countries (AU)

Objetivo: determinar la prevalencia de sobrepeso y obesidad en adolescentes de cinco países árabes, en relación con la edad el sexo. Métodos: se empleó una técnica de muestreo aleatorio, estratificado y por etapas para seleccionar a estudiantes de secundaria de cinco países árabes (Kuwait, Libia, Palestina, Siria y los Emiratos Árabes Unidos). La muestra total fue de 3.302 (1.584 chicos, 1.718 chicas). Se midieron el peso y la talla y se utilizó el índice de masa corporal para calcular la proporción de sobrepeso y obesidad basándonos en el estándar de la International Obesity Task Force (IOTF). Resultados: los adolescentes kuwaitíes mostraron la mayor prevalencia de sobrepeso y obesidad tanto en chicas como en chicos, en comparación con otros países. No hubo una tendencia en la proporción de sobrepeso y obesidad por sexo en ningún país de los incluidos en el estudio. Conclusión: la obesidad en adolescentes ha alcanzado un nivel crítico en los países árabes. Por lo tanto, existe la necesidad urgente de establecer programas para prevenir y controlar la obesidad en los escolares de estos países (AU)

No change in calcium absorption in adult Pakistani population before and after vitamin D administration using strontium as surrogate.

UNLABELLED: Vitamin D, parathyroid hormone levels and calcium absorption was assessed before and after cholecalciferol using Strontium as a surrogate. Increase in 25OHD, lowering of iPTH with no effect on Sr absorption was seen, suggesting the possibility that maximal Ca absorption had already been achieved in these volunteers. INTRODUCTION: This paper discusses the determination of calcium (Ca) absorption, using strontium (Sr) as a surrogate, before and after a single IM injection of vitamin D(3) (600,000 IU). METHODS: Baseline serum 25-hydroxyvitamin D (25OHD), Sr, Ca, P, and intact parathyroid hormone (iPTH) were determined in 53 fasting volunteers, followed by administrating (PO) 0.03 mM (4.8 mg/kg) SrCl(2) and collecting blood at 0.5, 1 and 4 h to determine the absorption (AUC(0 → t )) of Sr. Following the initial absorption test, volunteers received a single IM injection of 600,000 IU vitamin D(3). Two months later, the fasting serum and the Sr absorption test were repeated, as described above. RESULTS: The IM injection of vitamin D(3) caused a significant increase in fasting 25OHD (from 43.5 ± 19 to 66.1 ± 19.1 nmol/L (p < 0.001)) and a trend toward lower serum iPTH (from 59.8 ± 27.8 to 53 ± 31 ng/L). Fasting serum Ca and P remained unchanged. A higher 25OHD level failed (p = 0.32) to translate into a higher rate of Sr absorption. AUC(0 → 4 h) were almost identical before and after the IM injection of vitamin D(3). CONCLUSION: A single vitamin D(3) injection of 600,000 IU significantly increase mean 25OHD concentration and tended to lower iPTH concentrations in volunteers with initially low 25OHD status, suggesting to utilize this simple form of treatment to improve vitamin D status and to have a possible biological effect on Ca homeostasis. However, we found no obvious effect on Sr absorption, suggesting the possibility that maximal vitamin D-dependent Ca absorption had already been achieved in these volunteers at a lower vitamin D status.

Obesity among adolescents in five Arab countries; relative to gender and age.

OBJECTIVE: To determine the prevalence of overweight and obesity among adolescents in five Arab countries, relative to age and sex. METHODS: A multistage stratified random sampling technique was used to select the secondary school students from five Arab countries (Kuwait, Libya, Palestine, Syria and United Arab Emirates). The total sample was 3302 (1584 males, 1718 females). Weight and height were measured, and body mass index was used to calculate the proportion of overweight and obesity based on the International Obesity Task Force standard (IOTF). RESULTS: Kuwaiti adolescents showed the highest prevalence of overweight and obesity among both males and females, compared to their counterparts in other countries. There was no trend in the proportion of overweight and obesity by age in any of the countries included in the study. CONCLUSION: Adolescent obesity has reached a critical level in the Arab countries. Therefore there is an urgent need to establish programs to prevent and control obesity among schoolchildren in these countries.

Objective: To determine the prevalence of overweight and obesity among adolescents in five Arab countries, relative to age and sex. Methods: A multistage stratified random sampling technique was used to select the secondary school students from five Arab countries (Kuwait, Libya, Palestine, Syria and United Arab Emirates). The total sample was 3302 (1584 males, 1718 females). Weight and height were measured, and body mass index was used to calculate the proportion of overweight and obesity based on the International Obesity Task Force standard (IOTF). Results: Kuwaiti adolescents showed the highest prevalence of overweight and obesity among both males and females, compared to their counterparts in other countries. There was no trend in the proportion of overweight and obesity by age in any of the countries included in the study. Conclusion: Adolescent obesity has reached a critical level in the Arab countries. Therefore there is an urgent need to establish programs to prevent and control obesity among schoolchildren in these countries.

Extension of a PBPK model for ethylene glycol and glycolic acid to include the competitive formation and clearance of metabolites associated with kidney toxicity in rats and humans.

A previously developed PBPK model for ethylene glycol and glycolic acid was extended to include glyoxylic acid, oxalic acid, and the precipitation of calcium oxalate that is associated with kidney toxicity in rats and humans. The development and evaluation of the PBPK model was based upon previously published pharmacokinetic studies coupled with measured blood and tissue partition coefficients and rates of in vitro metabolism of glyoxylic acid to oxalic acid, glycine and other metabolites using primary hepatocytes isolated from male Wistar rats and humans. Precipitation of oxalic acid with calcium in the kidneys was assumed to occur only at concentrations exceeding the thermodynamic solubility product for calcium oxalate. This solubility product can be affected by local concentrations of calcium and other ions that are expressed in the model using an ion activity product estimated from toxicity studies such that calcium oxalate precipitation would be minimal at dietary exposures below the NOAEL for kidney toxicity in the sensitive male Wistar rat. The resulting integrated PBPK predicts that bolus oral or dietary exposures to ethylene glycol would result in typically 1.4-1.6-fold higher peak oxalate levels and 1.6-2-fold higher AUC's for calcium oxalate in kidneys of humans as compared with comparably exposed male Wistar rats over a dose range of 1-1000 mg/kg. The converse (male Wistar rats predicted to have greater oxalate levels in the kidneys than humans) was found for inhalation exposures although no accumulation of calcium oxalate is predicted to occur until exposures are well in excess of the theoretical saturated vapor concentration of 200mg/m(3). While the current model is capable of such cross-species, dose, and route-of-exposure comparisons, it also highlights several areas of potential research that will improve confidence in such predictions, especially at low doses relevant for most human exposures.

Characterization and anti-microbial susceptibility of gram-negative bacteria isolated from bloodstream infections of cancer patients on chemotherapy in Pakistan.

PURPOSE: Bloodstream infection remains a major cause of morbidity and mortality in patients undergoing treatment for cancer. Severe infections due to Gram-negative bacilli & staphylococci are common in cancer patients. Altered gut flora because of frequent antibiotic administration and damage of epithelial surfaces contribute to the development of infection. To access the use of new potent antibiotics against bloodstream infection in cancer patients and to determine the cross resistance of Gram-negative bacterial strains. MATERIALS AND METHODS: We studied the bacterial spectrum & antimicrobial susceptibility pattern of cephalosporins, fluoroquinolones, carbapenems and aminoglycosides against Gram-negative bacterial strains in cancer patients. The susceptibility was determined by broth dilution method according to National Committee for Clinical Laboratory Standards (NCCLS) now called Clinical Laboratory Standards Institute (CLSI) during study period (July 2006 to Jan 2007). RESULTS: A total of 60 Gram-negative bacterial blood cultures were examined. Among these, Pseudomonas aeruginosa was the most common (38%). The Minimum Inhibitory Concentration at which 50% (MIC 50 ) and 90% (MIC 90 ) of Enterobacteriaceae and P. aeruginosa inhibited were found. Resistance in P.aeruginosa against cefepime, meropenem, ciprofloxacin, ceftriaxone, tobramycin, cefoperazone and imipenem was 60%, 13%, 80%, 67%, 40%, 90% and 10% respectively while for Enterobacteriaceae 80%, 20%, 88%, 72%, 20%, 90% and four per cent resistance was observed. Meropenem was found to be the most effective antimicrobial against Gram-negative bacteria. CONCLUSION: High resistance observed in this study warrants the needs of surveillance of resistant pattern of antimicrobial agents. Due to increased level of drug resistance, carbapenem would be a prudent choice in high- risk cases.

Antimicrobial susceptibility patterns and characterization of clinical isolates of Staphylococcus aureus in immunocompromised cancer patients undergoing chemotherapy in Pakistan.

Cancer patients undergoing chemotherapy are highly prone to infections because of suppression of their immune system. in the present study, the activity of fluoroquinolones, cephalosporins, glycopeptides and oxazolidinones was evaluated in Staphylococcus aureus strains by broth dilution method according to Clinical and laboratory Standards institute (ClSi), USA guidelines. the frequency of methicillin-resistant S. aureus (mRSA) and methicillin-sensitive S. aureus (mSSA) strains was 67% and 33% respectively. The MIC(50 )and MIC(90 )of isolates were ciprofloxacin 8 and 32 microg/ml for mRSA, 8 and 16 microg/ml for mSSA, levofloxacin 8 and 16 microg/ml for mRSA and mSSA, gatifloxacin 4 and 16 microg/ml for mRSA and 4 and 8 microg/ml for mSSA. MIC(50 )and MIC(90 )of vancomycin and linzolid were 1 and 2 microg/ml, 2 and 4 microg/ml for both mRSA and mSSA strains respectively. this study shows a high prevalence of and resistance in mRSA. However, vancomycin and linezolid were highly active and could be used for treating mRSA infections.

Pharmacokinetics and bioavailability of diisopropanolamine (DIPA) in rats following intravenous or dermal application.

This study was conducted to determine the relative dermal bioavailability (absorption), distribution, metabolism, and excretion (ADME) of diisopropanolamine (DIPA), an alcohol amine used in a number of industrial and personal care products. Groups of 4 female Fischer 344 rats received either a single bolus i.v. dose of 19.0mg/kg (14)C-DIPA in water or a dermal application of 19.5mg/kg (14)C-DIPA in acetone to an area of 1cm(2) on the back and covered with a bandage. Time-course blood and excreta were collected and radioactivity determined. Urine was analyzed for DIPA and monoisopropanolamine (MIPA). Following i.v. administration, DIPA was rapidly cleared from the plasma and excreted into urine in a biexponential manner (t(1/2alpha), 0.4h; t(1/2beta), 2.9h). The levels of radioactivity in plasma dropped below the limit of detection 12h post-dosing. A total of 97+/-4% of the dose was actively excreted in urine by kidney, most ( approximately 71%) within 6h of dosing, virtually all as parent compound; renal clearance exceeded the glomerular filtration rate. Following dermal application, approximately 20% of the dose was absorbed in 48 h with the steady-state penetration rate of approximately 0.2%/h. Most (14.4%) of the applied radioactivity was excreted in urine at a relatively constant rate due to the presence of large amount of the (14)C-DIPA at the application site. Fecal elimination was <0.2% of the dose. The absorbed DIPA did not accumulate in tissues; only approximately 0.1% of the administered dose was found in liver and kidney. The absolute systemic dermal bioavailability (dose corrected AUC(dermal)/AUC(i.v.)) of (14)C-DIPA was 12%. The ADME of DIPA contrasts that of its diethanol analogue, diethanolamine, which displays a broad spectrum of toxicity in rats and mice. Toxicologically significant concentrations of DIPA are unlikely to be achieved in the systemic circulation and/or tissues as a result of repeated dermal application of products containing DIPA due to slow absorption from the skin, rapid unchanged elimination in urine, and majority of the products contain

Selected quality parameters of salmon and meat when fried with or without added fat.

AIM: To determine whether pan-frying (pork, beef and salmon) without oil or with different fats (olive oil, corn oil or a partially hydrogenated plant oil) or steaming (only salmon) have effects on the total fat content, the fatty acid pattern, lipid peroxidation, tocopherols and in particular for salmon on vitamin D(3) and astaxanthin. MATERIAL AND METHODS: Pork, beef patties and salmon were pan-fried (6 min each), beef fillet was pan-fried (5 min) with an additional braising period of 90 minutes and salmon was steamed for 12 minutes. Each pan-frying treatment was done with the above mentioned fats and without fat. Total fat was determined gravimetrically, the fatty acid pattern with GC, the tocopherols, astaxanthin and vitamin D(3) by using HPLC. RESULTS: The effects on the fat quality and quantity in the final products were related to the pan-frying fat used, however, the power of the outcome was depending on the surface to volume ratio. The highest increase in total fat was observed for pork, followed by the beef patties and the braised beef. The same has been assessed for the fatty acid pattern. Tocopherols changed according to the oil used, in particular gamma-tocopherol significantly increased for each preparation after the use of corn oil. Only in pork an increase in lipid oxidation of the oil preparations has been observed. Vitamin D(3) in salmon significantly decreased after heat treatment, however a 150 g salmon portion would provide between 13.9 and 14.7 mug Vitamin D(3) which is around five times more than the average daily intake. CONCLUSION: Pan-frying without fat can be recommended for the daily use, since the total fat intake is too high in developed countries and one main task of nutritional recommendations is to reduce the total fat intake. When pan-fried with fat, the choice of the fat is of high importance since it directly influences the quality and the flavour of the final product. In order to increase the fat quality from nutritional point of view only oils of plant or vegetable origin should be used in households. Pan-fried salmon is a good source of Vitamin D(3).

Lipid oxidation of beef fillets during braising with different cooking oils.

Effects of braising without oil and with different cooking oils (olive oil, corn oil and partially hydrogenated plants oil) on the susceptibility to lipid oxidation in beef fillets (psoas major) were evaluated. The beef fillets were pan-fried without oil or with the respective oils for five min, followed by 90 min steam cooking (braising). Lipid oxidation status of the samples and the cooking residues was evaluated by peroxide value (PV), acid value (AV), p-Anisidine value (p-AnV), as well as the alteration of the tocopherol content. Total lipids and the individual fatty acid pattern were analyzed in order to determine the impact of the frying medium as well as the cooking procedures on the fat of the braised samples. The decrease in PV simultaneous with the significant increase in p-AnV indicated the progression of lipid oxidation. Tocopherol and fatty acid contents of all the investigated samples exhibited modifications mainly due to the influence of the frying medium and braising process. Although there was a significant change in lipid oxidation parameters, there is no risk in consuming such braised meat.

Oral absorption, metabolism and excretion of 1-phenoxy-2-propanol in rats.

1. This study was designed to determine the absorption, metabolism and excretion of 1-phenoxy-2-propanol in Fischer 344 rats following oral administration in an effort to bridge data with other propylene glycol ethers. 2. Rats were administered a single oral dose of 10 or 100 mg kg(-1) 14C-1-phenoxy-2-propanol as a suspension in 0.5% methyl cellulose ether in water (w/w). Urine was collected at 0-12, 12-24 and 24-48 h and faeces at 0-24 and 24-48 h post-dosing and the radioactivity was determined. Urine samples were pooled by time point and dose level and analysed for metabolites using LC/ESI/MS and LC/ESI/MS/MS. 3. The administered doses were rapidly absorbed from the gastrointestinal tract and excreted. The major route of excretion was via the urine, accounting for 93 +/- 5% of the low and 96 +/- 3% of the high dose. Most of the urinary excretion of radioactivity occurred within 12 h after dosing; 85 +/- 2% of the low and 90 +/- 1% of the high dose. Total faecal excretion remained < 10%. Rats eliminated the entire administered dose within 48 h after dosing; recovery of the administered dose ranged from 100 to 106%. Metabolites tentatively identified in urine were conjugates of phenol (sulphate, glutathione) with very low levels (< 2%) of hydroquinone (glucuronide), conjugates of parent compound (glucuronide, sulphate) and a ring-hydroxylated metabolite of parent. There was no free parent compound or phenol in non-acid-hydrolysed urine. In acid-hydrolysed urine, 61% of the dose was identified as phenol and 13% as 1-phenoxy-2-propanol. Although the parent compound was stable to acid hydrolysis, some of the phenol in acid hydrolysed urine may have arisen from degradation of acid-labile metabolite(s) as well as hydrolysis of phenol conjugates. 4. Rapid oral absorption, metabolism and urinary excretion of 1-phenoxy-2-propanol in rats were similar to other propylene glycol ethers.

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.

Differential and non-uniform tissue and brain distribution of two distinct 14C-hexachlorobiphenyls in weanling rats.

Excretion and tissue retention of a coplanar and a non-coplanar hexachlorobiphenyl (HxCB) were determined 48 h after a single intraperitoneal (ip) dose of 8 mg/kg radiolabeled [14C]-HxCBs to weanling male and female Long-Evans rats. The objective was to understand the involvement of initial target organs of chlorobiphenyl (CB) accumulation following acute exposure in immature animals. During the short interval, both HxCBs remained sequestered predominantly in mesenteric fat (compared to subcutaneous fat) and less than 1% of the doses were excreted. Excretion was 4- to 8-fold lower than adult rats. Coplanar CB 169 (3,3',4,4',5,5'-HxCB) did not accumulate appreciably in the brain, but was retained at 3-fold higher levels in the liver than was non-coplanar CB 153 (2,2',4,4',5,5'-HxCB). Accumulation of 14C-CB 153 in brains was 4- to 9-fold higher than that of 14C-CB 169 and was adequate to detect non-uniform distribution in serial cryostat sections by phosphor imaging autoradiography. The autoradiographs showed a higher CB 153-derived radioactivity associated with fiber tracts throughout the brain. Specifically, the corpus callosum, internal and external capsules, medial lemniscus, tegmentum of the mesencephalon and metencephalon, and cerebellar peduncles showed significantly higher 14C-CB 153 than the other structures. The 14C-CB 153 was not found in the ventricular system and vascular spaces. These results suggest for the first time that an ortho-substituted PCB congener accumulated preferentially in brain in a structure-specific manner when compared to a non-ortho-substituted PCB congener.

Toxicity and tissue distribution of 2,2',4,4'- and 3,3',4, 4'-tetrachlorobiphenyls in houseflies.

Insects selectively retain different polychlorinated biphenyls (PCBs) which are then contributed to the food chain. To quantitate specific differences, adult female houseflies (Musca domestica L.) were topically dosed with 0.5 microgram of two structurally distinct PCB congeners (14C-2,2',4,4'-tetraCB or 14C-3,3',4,4'-tetraCB). Total radioactivity in the acetone rinse of intact flies, several tissues, and excrement was determined at 11 time points over a 48-h period. Ninety-seven percent of the applied 2,2',4,4'-tetraCB disappeared from the surface following an initial rapid absorption of 79% within 3 h. The absorbed 2,2',4,4'-tetraCB was immediately found within the thoracic cuticle, then spreading laterally to the abdominal cuticle and head, through the wax layers, or penetrating to the alimentary canal and ovaries. Penetration of 3,3',4, 4'-tetraCB was markedly slower; even though 87% of the applied dose was absorbed within 48 h, only 19% of the dose penetrated into the fly body within the first 3 h. This PCB very slowly distributed into the tissues. Toxicities of the sublethal doses were determined by monitoring changes in activity of houseflies following dosing with 0. 5 microg of radioactive PCBs. Flies treated with 2,2',5-triCB and 3, 3',4,4'-tetraCB remained very active, whereas 2,2',4, 4'-tetraCB-treated flies were less active, consistent with the previously reported toxicity of this congener.

Short-term distribution, metabolism, and excretion of 2,2',5-tri-, 2, 2',4,4'-tetra-, and 3,3',4,4'-tetrachlorobiphenyls in prepubertal rats.

The excretion and tissue retention of three 14C-labeled lower chlorinated biphenyls were examined in prepubertal male and female Sprague-Dawley rats following IV administration. Urine and feces were collected individually at different time intervals up to 72 h for pharmacokinetic analyses. After 72 h, different organs were removed and extracted in acetone:hexane (1:1, v/v) to determine radioactivity. Within the first 10 h after dosing, 2,2', 5-trichlorobiphenyl (PCB 18) was rapidly excreted in urine (8-18% of the administered dose), whereas only 0.6-0.8% of 2,2',4, 4'-tetrachlorobiphenyl (PCB 47) and 0.3-0.8% 3,3',4, 4'-tetrachlorobiphenyl (PCB 77) were found in urine during this time period. The half-life of elimination was shortest for PCB 18 (37.5 to 49.2 h). The half-lives for PCB 47 and PCB 77 were 351 to 672 h and 152 to 186 h, respectively. The cumulative total excretion (urinary + fecal) of PCB 18 within 72 h was 51-62%, of PCB 77 was 22-25%, and of PCB 47 was 7-10%. No parent PCBs were detected in urine. PCB 47 accumulated preferentially in adipose tissues (subcutaneous fat > mesenteric fat); relatively high levels of PCB 47 were also found in adrenals, ovaries, lungs, liver, and skin. The highest concentration of PCB 77 was found in serum, followed by adipose tissues. Very low concentrations of PCB 18 were found in most tissues; the highest being found in serum, followed by ovaries and adrenal glands. This study suggests that prepubertal rats retain higher short-term serum levels and have lower excretion rates than adult rats.

Use of a medium-term liver focus bioassay to assess the hepatocarcinogenicity of 1,2,4,5-tetrachlorobenzene and 1,4-dichlorobenzene.

1,2,4,5-Tetrachlorobenzene (TeCB) and 1,4-dichlorobenzene (DCB) are important environmental contaminants that have been used extensively for a variety of industrial applications. Limited data are available in the literature regarding the carcinogenicity of TeCB. DCB has been shown to cause renal adenocarcinomas in rats and hepatic adenomas and carcinomas in mice at high doses in a 2-year study. In the studies presented here, we report that TeCB can promote the formation of preneoplastic foci and DCB cannot in a medium-term initiation/promotion assay. These results suggest that TeCB is a liver tumor promoter and that DCB is not at fairly low doses (0.1 and 0.4 mmol/kg per day).

An audit on hospital management of bronchial asthma.

Medical audit is a new concept in developing countries like Pakistan. We carried out this retrospective study on bronchial asthma. The purpose was to see if care given to patient with asthma meets the accepted international standard or not. During this audit several deficiencies were found. Documentation in notes about signs indicating severity of asthma was very poor. Peak flow recording in the notes was also very deficient. There was no documentation in notes whether inhalers technique of the patients has been checked or not. This audit shows that care given to asthma patients is far from satisfactory and we clearly need to improve in order to reach the accepted international standards.

Toxicities of 2,2',4,4'- and 3,3',4,4-tetrachlorobiphenyls to house flies at different ages and enzyme levels.

Two tetrachlorobiphenyls (2,2',4,4'-tetraCB and 3,3',4,4'-tetraCB) had different effects on the longevity of adult female house flies (Musca domestica), depending on enzyme levels at dosing. Twenty-four-hour acute toxicities of the two tetrachlorobiphenyls were also compared with one trichlorobiphenyl (2,2',5-triCB) at different enzyme levels. 2,2',4,4'-tetraCB killed more than 90% of the flies within 12 h at the highest dose (1,667 ppm, micrograms/g); however, the toxicity of the moderate dose (1,250 ppm) was age-dependent and greater in 1- and 15-day-old flies and lower in 5-day-old flies. Daily mortality patterns of the lower doses (390 and 833 ppm) were similar to the control. LT50s (time for 50% death) were also different in different age groups at the moderate dose. The toxicity of 3,3',4,4'-tetraCB was similar to the control in all age groups, with a slight increase in the early mortalities and a decrease in the LT50s at the highest (1,200 ppm) dose. The twenty-four-hour lethality of 2,2',4,4'-tetraCB was very high, even at the lower doses in 1- and 15-day-old flies. Lower doses were least toxic at day 5, when the levels of cytochrome P450 enzymes were at the highest. On the other hand, the acute toxicity of 2,2',5-triCB increased from 5 and 15% in 1- and 15-day-old flies, respectively, to about 50% in 5-day-old flies, suggesting bioactivation of 2,2',5-triCB. The acute toxicity of 3,3',4,4'-tetraCB was negligible in all ages of house flies.

Influence of enzyme levels on the toxicity and in vitro metabolism of 2,2',5-trichlorobiphenyl in houseflies.

Adult female houseflies (Musca domestica) were topically dosed with 10, 15, and 20 micrograms of 2,2',5-trichlorobiphenyl (PCB-18) in acetone at 1, 5, and 15 days following emergence. These doses caused a significant decrease in the mean survival time in 5-day-old flies. LT50's (time for 50% death) were dramatically reduced in 5-day-old flies, whereas no significant difference was found at any treatment level in 15-day-old flies. Abdomenal microsomal enzyme levels were determined by the rate of O-dealkylation of (p-nitrophenyl)ethyl ether for 1-, 5-, 11-, and 15-day-old female houseflies. The highest levels were found in 5-day-old flies and the lowest in 15-day-old flies. The greatest metabolism of PCB-18 by housefly microsomes also occurred in 5-day-old flies. The enzyme levels, metabolism, and toxicity suggest that PCB-18 is bioactivated to a product(s) which reduces the mean survival time of houseflies.