Uptake,metabolism, and elimination of methylene chloride vapor by humans

Methylene chloride (CH₂Cl₂) is extensively utilized both in industry and in commerce. The finding that CH₂Cl₂ was metabolized to carbon monoxide (CO) by humans and experimental animals prompted us to measure blood carboxyhemoglobin saturations in workers exposed to CH₂Cl₂ and to conduct controlled experimental human exposures. Experimental exposures to CH₂Cl₂ vapor were carried out with sedentary nonsmokers for $\text{7}\text{1}\text{2}$ hr at 50, 100, 150, or 200 ppm or for $\text{7}\text{1}\text{2}$ hr each day at 100, 150, or 200 ppm for 5 consecutive days. During controlled exposures as much as 70% of the inhaled vapor was absorbed by the pulmonary route. Between 25 and 34% of the absorbed CH₂Cl₂ was excreted in the expired air as CO during and after the exposure and less than 5% was eliminated unchanged in the expired air after the exposure. Exposure to 50, 100, 150, or 200 ppm of CH₂Cl₂ produced peak blood carboxyhemoglobin saturations of 1.9, 3.4, 5.3, and 6.8%, respectively. Peak end tidal air and blood concentrations of CH₂Cl₂ and CO were essentially unchanged during repeated exposures. The average peak blood carboxyhemoglobin saturation for workers occupationally exposed to CH₂Cl₂ vapor was 3.9%. The above findings show that end tidal air and blood concentrations of CH₂Cl₂ and CO are directly proportional to the magnitude of the exposure and that an 8-hr exposure to 100 ppm of CH₂Cl₂ vapor will produce a blood carboxyhemoglobin saturation of about 3%, less than the increase in blood carboxyhemoglobin saturations produced by an exposure to CO at its recommended TLV of 35 ppm.     

Alteration of carbon monoxide and hypoxic hypoxia-induced lethality following phenobarbital, chlorpromazine, or alcohol pretreatment

Mice were pretreated with phenobarbital, chlorpromazine, or alcohol prior to exposure to 1900 ppm carbon monoxide (CO) or 7.5% oxygen (O₂) environments. Pretreatment for 1 hr with chlorpromazine or ethanol increased the lethality of mice exposed to both CO and 7.5% O₂, while 1-hr phenobarbital pretreatment had no effect on CO lethality but increased 7.5% O₂ lethality. Changes in carboxyhemoglobin concentrations that were observed were inconsistent with the alteration in CO lethality. Studies of red blood cell 2,3-diphosphoglycerate concentrations and rate of carboxyhemoglobin formation in vitro showed that the apparent affinity of hemoglobin for oxygen and CO remained unchanged following drug or alcohol pretreatments. The different effects of the pretreatments on CO and 7.5% O₂ lethality and the lack of correlation of CO lethality with carboxyhemoglobin concentrations suggests that there are other factors besides extracellular events directly associated with oxygenation of tissues which are critical determinants of the lethal potential of CO or 7.5% O₂.     

On the metabolic acidosis of ethylene glycol intoxication.

Methylene chloride was administered to rats by vaporization in a closed rebreathing system. Doses ranged from 80 to 800 μmol/kg. The rate of CO production was measured and the total amount of CO formed in excess of the endogenous amount was calculated. Addition of CH₂Cl₂ to the gas phase caused an initial increase in CO production to about 35 times the endogenous rate at all doses given. The total amount of CO formed when all CH₂Cl₂ was metabolized depended on the dose given, amounting to about 0.48 mol of CO/mol of CH₂Cl₂ administered. All dihalogenated methanes caused an increase in CO production and a decrease in methane production. At 100 μmol/kg the order of decreasing effect on both the initial production rate and the final amount of CO accumulated was CH₂Br₂ > CH₂Cl₂ > CH₂BrCl > CH₂I₂. Methane production by the intestinal bacteria was inhibited in the order CH₂BrCl > CH₂Br₂ > CH₂Cl₂ > CH₂I₂. The CO production of germ-free rats is increased by CH₂Cl₂ to the same extent as with controls. The data suggest that a low dose of dihalogenated methane causes substrate saturation of the enzyme system involved in CO production. Large doses of methylene chloride cause a progressive increase in the rate of CO production over several hours. Such results suggest that substrate-induced enzyme formation occurs when the concentration of methylene chloride is maintained.     

A physiological model for the pharmacokinetics of methylene chloride in B6C3F1 mice following i.v. administrations

A physiologic mathematical model was developed to describe the time course of¹⁴C-methylene chloride (¹⁴CH₂Cl₂) distribution and elimination in mice following single i.v. administrations of 10 and 50mg/kg. A whole-body model was used to simulate¹⁴CH₂Cl₂ concentrations in blood and tissues, pulmonary clearance of unchanged¹⁴CH₂Cl₂, and metabolic conversion to¹⁴CO₂ and¹⁴CO as monitored by the appearances of these metabolites in expired breath. This diffusion-limited model was identified via a sequential optimization scheme using hybrid models for each compartment. Pulmonary elimination of unchanged¹⁴CH₂Cl₂ was modeled as a linear process while hepatic metabolism of¹⁴CH₂Cl₂ to the compounds¹⁴CO₂and¹⁴CO was described by a saturable metabolic rate term. The model adequately described the dose dependence in methylene chloride distribution and metabolism when simulations were compared to experimental data.     

Biological oxidation of [14C]methylene chloride to carbon monoxide and carbon dioxide by the rat

Rats were exposed to ¹⁴CH₂Cl₂ vapor in a closed rebreathing system. The total amount of respiratory ¹⁴CO₂ and ¹⁴CO was accumulated for periods up to 15 hr after dosing. These two metabolic products accounted on the average for 76% of the radioactivity of the ¹⁴CH₂Cl₂ given. The major portion, 47%, was found as ¹⁴CO whose specific activity was close to that of the administered ¹⁴CH₂Cl₂. This suggests a nearly direct conversion of CH₂Cl₂ to CO. Approximately 29% of the radioactivity was recovered in the expired CO₂. The oxidation of methylene chloride to CO and CO₂ was similar qualitatively and quantitatively for male and female animals. The data suggest that methylene chloride acts as a direct substrate for metabolic formation of CO rather than by stimulating the conversion of endogenous carbon sources to CO.     

Fate and disposition of [ 14Ia1 methylene chloride in the rat.

[¹⁴C]Methylene chloride (¹⁴CH₂Cl₂) was administered ip to Sprague-Dawley rats at doses ranging from 412 to 930 mg/kg. Animals were sacrificed 2, 8, and 24 hr after dosing. CH₂Cl₂ was largely eliminated in the breath unchanged during the first 2 hr. A fraction of the original dose was metabolized to carbon monoxide (CO), carbon dioxide (CO₂), and an uncharacterized metabolite. At 24 hr 91.5% of the dose was eliminated in the breath unchanged, 2% was eliminated as CO, 3% as CO₂, 1.5% as an uncharacterized metabolite, 1% was excreted in urine, and 2% remained in the carcass. Although the dissemination of radioactivity was widespread in rat tissue, the overall tissue uptake of ¹⁴C was relatively small. The highest tissue specific activities were found in the liver, kidneys, and adrenal glands. There was no significant accumulation of radioactivity in the fat. In a separate study serum and tissue formaldehyde concentrations (CH₂O) were measured in rats dosed with CH₂Cl₂. A substantial increase in serum CH₂O (62%) and a decrease in liver CH₂O (64%) were noted in rats treated with CH₂Cl₂. Formaldehyde concentrations in other tissues remained unchanged. ¹⁴CH₂O was not found in the breath, serum, or tissues of rats treated with ¹⁴CH₂Cl₂. Apparently the changes in serum and liver CH₂O were physiologically induced by CH₂Cl₂. There was no evidence from these experiments that CH₂Cl₂ was metabolized to CH₂O.     

The effects of spironolactone on the biliary excretion of mercury,cadmium, zinc,and cerium in rats

The effect of spironolactone (Sp) pretreatment on the biliary excretion of intravenously injected heavy metals (mercury, cadmium, zinc and cerium) was investigated in rats, using five metal compounds (four inorganic metals in chloride form, and methyl mercuric chloride). The oral administration of Sp ($\text{5 mg}\text{100 g}$) 1–3 hr before the bile excretion study increased the biliary recovery of mercury more than ten times over a period of 4 hr in rats injected with mercuric chloride, but did not increase the biliary excretion of the other three metals (Cd, Zn and Ce). Multiple-dose pretreatment (2 doses a day for 3 days) also increased the biliary excretion of mercury but much less than in the acutely treated rats. Cadmium excretion was significantly decreased by multiple dose pretreatment. Sequential nuclear imagings after intravenous injection of ¹⁹⁷HgCl₂, demonstrated clear differences in the tissue distribution of mercury between control and Sp-treated rats.     

Factors affecting exposure to nicotine and carbon monoxide in adult cigarette smokers

Exposure to cigarette smoke among smokers is highly variable. This variability has been attributed to differences in smoking behavior as measured by smoking topography, as well as other behavioral and subjective aspects of smoking. The objective of this study was to determine the factors affecting smoke exposure as estimated by biomarkers of exposure to nicotine and carbon monoxide (CO). In a multi-center cross-sectional study of 3585 adult smokers and 1077 adult nonsmokers, exposure to nicotine and CO was estimated by 24 h urinary excretion of nicotine and five of its metabolites and by blood carboxyhemoglobin, respectively. Number of cigarettes smoked per day (CPD) was determined from cigarette butts returned. Puffing parameters were determined through a CreSS® micro device and a 182-item adult smoker questionnaire (ASQ) was administered. The relationship between exposure and demographic factors, smoking machine measured tar yield and CPD was examined in a statistical model (Model A). Topography parameters were added to this model (Model B) which was further expanded (Model C) by adding selected questions from the ASQ identified by a data reduction process. In all the models, CPD was the most important and highest ranking factor determining daily exposure. Other statistically significant factors were number of years smoked, questions related to morning smoking, topography and tar yield categories. In conclusion, the models investigated in this analysis, explain about 30-40% of variability in exposure to nicotine and CO.     

Consequences of Brief Exposure to High Concentrations of Carbon Monoxide in Conscious Rats

Exposure to high-concentration carbon monoxide (CO) is of concern in military operations. Experimentally, the physiologic manifestations of a brief exposure to elevated levels of CO have not been fully described. This study investigated the development of acute CO poisoning in conscious male Sprague-Dawley rats (220–380 g). Animals were randomly grouped (n = 6) and exposed to either air or 1 of 6 CO concentrations (1000, 3000, 6000, 10,000, 12,000, or 24,000 ppm) in a continuous air/CO dynamic exposure chamber for 5 min. Respiration was recorded prior to and during exposures. Mixed blood carboxyhemoglobin (COHb) and pH were measured before and immediately after exposure. Before exposure the mean baselines of respiratory minute volumes (RMVs) were 312.6 ± 43.9, 275.2 ± 40.8, and 302.3 ± 39.1 ml/min for the 10,000, 12,000 and 24,000 ppm groups, respectively. In the last minute of exposure RMVs were 118.9 ± 23.7, 62.1 ± 10.4, and 22.0 ± 15.1% (p < .05) of their mean baselines in these 3 groups, respectively. Immediately after exposure, blood COHb saturations were elevated to 60.16, 63.42, and 69.37%, and blood pH levels were reduced to 7.43 ± 0.09, 7.25 ± 0.05, and 7.13 ± 0.04 in the 3 groups, respectively. Mortality during exposure was 1/12 in the 12,000 ppm group and 4/12 in the 24,000 ppm group. Deaths occurred close to the end of 5 min exposure. In each animal that died by exposure, pH was <6.87 and COHb saturation was >82%. Blood pH was unaltered and no death occurred in rats exposed to CO at concentrations <6000 ppm, although COHb saturations were elevated to 14.52, 29.94, and 57.24% in the 1000, 3000, and 6000 ppm groups, respectively. These results suggest that brief exposure to CO at concentrations <10,000 ppm may produce some significant physiological changes. However, exposure to CO at concentrations >10,000 ppm for brief periods as short as 5 min may change RMV, resulting in acute respiratory failure, acidemia, and even death.     

Existence of a threshold for hydroxyl radical generation independent of hypoxia in rat striatum during carbon monoxide poisoning

We examined the role of hypoxia in the carbon monoxide (CO)-induced generation of the hydroxyl radical (^•OH) in the striatum, which could contribute to brain damage due to CO poisoning. Exposure of free-moving rats to 1,000 and 3,000 ppm CO or 8 and 5% O₂ for 40 min caused concentration-dependent hypoxic conditions in terms of carboxyhemoglobin (COHb), deoxyhemoglobin, oxyhemoglobin, and O₂ contents in arterial blood. The hypoxic conditions seemed comparable between 3,000 ppm CO and 5% O₂, although alterations of pH and partial O₂ pressure (PO₂) were complex and concentration independent. In the striatum, CO and low O₂ decreased tissue PO₂ levels in a concentration-dependent and concentration-independent manner, respectively, but levels at the end of exposure were comparable among all groups. This was also the case for the increase in striatal blood flow. Although the increases in extracellular glutamate (excitatory), taurine (inhibitory), and alanine (non-neurotransmitter), in the striatum in response to CO and low O₂ were complex, 3,000 ppm CO and 5% O₂ had comparable effects. Thus, 3,000 ppm CO and 5% O₂ seemed to induce comparable hypoxic conditions. Nevertheless, the former more strongly stimulated ^•OH generation in the striatum than the latter. In addition, in contrast to low O₂ which caused a concentration-dependent increase in ^•OH, 1,000 ppm CO had no effect. The findings suggest that striatal ^•OH generation due to CO poisoning may be independent of hypoxia per se and that a threshold might exist.     

Disposition kinetics of spironolactone in hepatic failure after single doses and prolonged treatment

Summary Six male patients with histologically characterised, decompensated liver disease who had not previously received spironolactone, were given orally Aldactone^® 7 mg/kg with³H-spironolactone 100 µCi. The kinetics of the drug were studied in plasma and urine for 6 days. Then, Aldactone^® 7 mg/kg was given daily for 12 consecutive days, and the pharmacokinetics of a single dose of³H-spironolactone were re-examined. The kinetics of total radioactivity, as well as of fluorigenic metabolites in plasma, after the first single dose of spironolactone did not differ in patients and normal test subjects; similar percentages of the dose given were excreted within 6 days in urine from patients (47.47±4.88%) and from controls (53.68±2.04%). The kinetics of CH₂Cl₂/H₂O distribution coefficients of labelled material in plasma and urine, as well as TLC analysis of the CH₂Cl₂ soluble fraction, revealed no significant differences from controls. After treatment for 12 days with spironolactone, 4 out of 6 patients showed marked acceleration in the rate of elimination of radioactivity from plasma and a corresponding increase in excretion of labelled compounds in urine. Analysis of the excretion products in urine revealed proportionally increased excretion and no evidence of selective induction of a single degradation step. In contrast, delayed elimination was observed in the 2 other patients after 12 days' treatment. However, this was due to dehydration and oliguria caused by over-treatment with the diuretic.     

Elimination of Recently Absorbed Methyl Mercury Depends on Age and Gender

Abstract: The toxicokinetics of some toxic metals have been demonstrated to depend on the age of the exposed individuals. Most studies focused solely upon age-dependent differences in degree of absorption. The present study aimed at investigating possible age-dependent differences in elimination of CH₃HgCl using ²⁰³Hg and repeated whole-body counting of live mice to quantitate the whole-body retention. With increasing age at the time of exposure to a single oral dose of CH₃HgCl, the rate of elimination more than doubled in male mice. As intestinal absorption of CH₃HgCl is almost complete, the findings must pertain either to an age-related increased excretion capacity or an age-dependent change in the excretion mechanism. To study whether saturation of the excretion mechanism could explain this observation, groups at different age were supplemented with non-labeled CH₃HgCl in the drinking water during a two weeks observation period after administration of a single dose of CH₃²⁰³HgCl. Supplementation did not influence the rate of elimination of CH₃HgCl in mature males. Accordingly, the mechanism causing the observed age-dependent change in elimination rate is not a matter of saturation but an age-dependent development of a more efficient mechanism for CH₃HgCl elimination. Further, as elimination of mercury absorbed during a prolonged period of exposure through drinking water was not influenced by age, the critical step for the age-dependent mechanism for elimination of CH₃HgCl seems to be the initial absorption and distributional phase after exposure and most likely involves the hepatic handling of methyl mercury.     

长期接触低浓度一氧化碳作业工人血中碳氧血红蛋白及血气分析

对８３例长期接触低浓度一氧化碳（ＣＯ）作业工人进行了血中碳氧血红蛋白（ＣＯＨｂ）含量的测定，血气分析及健康状况调查，并与６８名无毒害作业工人为对照做了对比分析。结果表明：①ＣＯ作业工人血中ＣＯＨｂ含量显著高于对照组，且就使血中ＣＯＨｂ升高而言，职业性接触ＣＯ显著高于吸烟，因此，ＣＯＨｂ是一个很好的接触指标；②ＣＯ作业工人末梢动脉血氧分压降低，并伴有神经衰弱和消化道障碍等症状。     

Evaluation of Biological Activity of Turkish Plants. Rapid Screening for the Antimicrobial,Antioxidant, and Acetylcholinesterase Inhibitory Potential by TLC Bioautographic Methods

Using thin-layer chromatography (TLC) bioautography, a total of 58 extracts from various organs (aerial parts, leaves, flowers, fruits, roots) of 16 Turkish plants were tested for their antibacterial, antifungal, acetylcholinesterase inhibitory, antioxidant, and radical scavenging activities. The hexane, CHCl₃/CH₂Cl₂, water, and total MeOH extracts were used. No activity was observed against two Gram-negative bacteria (Escherichia coli and Pseudomonas aureginosa) and the yeast Candida albicans. However, 23 plant extracts, mostly the CHCl₃/CH₂Cl₂ and H₂O-solubles, inhibited the growth of all five Gram-positive bacteria tested, Micrococcus luteus, Bacillus subtilis, Bacillus cereus, Staphylococcus aureus, and Staphylococcus epidermidis. Of the active extracts, the CHCl₃-soluble of the roots of Putoria calabrica (L. fil) DC (Rubiaceae) displayed the highest antibacterial potential. The majority of the CHCl₃/CH₂Cl₂ crude extracts also appeared to inhibit acetylcholinesterase on TLC plates at 100 µg/spot concentration. Particularly active samples were the middle polarity extracts (CHCl₃/CH₂Cl₂) of the leaves of Rhododendron smirnovii Trautv., R. ponticum L., and R. ungernii Trautv. (Ericaceae). β-Carotene, β-carotene/linoleic acid mixture, and 2,2-diphenyl-l-pieryhydrazyl (DPPH) solutions sprayed onto TLC plates were used for detecting antioxidant and radical scavenging properties of the crude extracts. Antioxidant and radical scavenging activities were found to be predominant in highly polar extracts. The water-solubles of all Rhododendron (Ericaceae) and Phlomis (Lamiaceae) species presented the most significant activity.     

Effects of continuous inhalation of dichloromethane in the mouse: morphologic and functional observations

Continuous inhalation of 5000 ppm CH₂Cl₂ caused balloon degeneration, transient severe fatty change and partial inhibition of leucine incorporation into liver proteins of 20–32 g female mice of the ICR stain. The earliest lesion was identified at 12 hr of exposure and consisted of dissociation of polyribosomes and swelling of hepatocyte rough endoplasmic reticulum (so-called “balloon” degeneration). Balloon degeneration peaked in severity at 2 days of exposure and then partially reversed. Liver fatty change was also partially reversible. There was a 12-fold increase in liver triglycerides with 3 days of exposure, but at 1 wk of continuous exposure liver triglycerides were two to three times control values. Necrosis was observed in a few isolated hepatocytes.     

Estimating the hazards of less hazardous cigarettes. II. Study of cigarette yields of nicotine, carbon monoxide, and hydrogen cyanide in relation to levels of cotinine, carboxyhemoglobin, and thiocyanate in smokers

Yields of chemical constituents such as tar, nicotine, CO, and HCN defined by smoking machines are commonly assumed to provide a reasonable indication of the relative hazard associated with smoking a given brand of cigarette. Results reported here suggest that this assumption should be carefully reexamined. A total of 240 subjects, representing a wide range of smoking and brand characteristics, were recruited for an investigation of possible relations between brand yields and exposure (levels of carboxyhemoglobin, breath CO, plasma cotinine, plasma thiocyanate, and saliva thiocyanate). Exposure was highly correlated with consumption (number of cigarettes per day), but their was no correlation between any estimate of exposure and brand yield when level of consumption was held constant. In addition, a comparison of levels of carboxyhemoglobin and plasma thiocyanate for 16 smokers of "low-hazard" and 15 smokers of "high-hazard" cigarette brands revealed little difference between the two groups, even though average cigarette yields differed as much as 2- to 3-fold. A possible explanation for the results may be that current values for average puff volume, duration, and interval differ significantly from those used in programming smoking machines, particularly in the case of brands with low nicotine delivery.     

Antitumor effects of bis-thiosemicarbazones— inhibition of deoxyribonucleic acid synthesis in vitro

A group of bis-thiosemicarbazones was evaluated for potential antitumor activity, using the L1210 murine leukemia in cell culture. Drug levels required to inhibit DNA synthesis by 50 per cent, under standard conditions, were determined. The most potent of the agents examined had the structure X[CH₂CR₁=NNHCSNHR₂]₂ where X = C or S and R₁ = R₂ = CH₃. Optimal activity was also obtained with R₁ = H and R₂ = CH₃ only when X = S. The most potent derivatives inhibited DNA synthesis by 50 per cent within 10 min at 10^?6 M levels (id₅₀). Metal chelates of several compounds tested were extremely potent inhibitors of DNA synthesis ($\text{id}{}_{50}\text{= 10}{}^{\mathrm{?7}}\text{M or less}$). Insolubility in water and short duration of action in vivo may limit effectiveness of the bis-thiosemicarbazones.     

Studies of the metabolism of N-methyl containing anti-tumour agents: 14CO2 breath analysis after administration of 14C-labelled N-methyl drugs, formaldehyde and formate in mice

The ¹⁴CO₂; content of the breath was analysed after administration of the following N-¹⁴ CH₃ labelled drugs to mice: aminopyrine, hexamethylmelamine (HMM), pentamethylmelamine (PMM), procarbazine and caffeine. Except for aminopyrine, the ¹⁴CO₂; exhalation rate plots declined monophasically with half lives of 91 min ([¹⁴C]-HMM), 97 min ([¹⁴C]-PMM), 68 min ([¹⁴C]procarbazine) and 92 min ([¹⁴C]caffeine). The ¹⁴CO₂ exhalation rate peaked rapidly after aminopyrine administration and declined bi-phasically with an initial $\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}$ of 15 min and a terminal $\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}$ of 126 min. The ¹⁴CO₂; plots after both [¹⁴C]-HMM and [¹⁴C]aminopyrine were influenced by pre-treatment of mice with proadifen. Pretreatment with phenobarbitone shortened the $\text{t}{}_{\mathrm{<mtext>1</mtext><mtext>2</mtext>}}$ of the ¹⁴CO₂ appearance rate after [¹⁴C]HMM by 24% but did not change the ¹⁴CO₂ curve after administration of [¹⁴C] aminopyrine. The ¹⁴CO₂ exhalation rate plots after administration of H¹⁴CHO and H¹⁴COOH were virtually identical with that obtained after [¹⁴C]aminopyrine and not influenced by either proadifen or phenobarbitone pretreatment. The ¹⁴CO₂ exhalation rate profile obtained on metabolism of [¹⁴C]aminopyrine in mice thus appears to be determined by the rate of the oxidation of formaldehyde or formate to CO₂. Only 24% of the label injected with the N-methyl moieties of [¹⁴C]HMM and 21% of the label in [¹⁴C]procarbazine were exhaled as ¹⁴CO₂, whereas 49% of the N-¹⁴CH₃ in [¹⁴C]aminopyrine were metabolized to ¹⁴CO₂. It remains to be determined whether this difference and the difference in the shapes of the ¹⁴CO₂ exhalation profiles obtained with the cytotoxic N-¹⁴CH₃ drugs as compared to [¹⁴C]aminopyrine, are related to the biochemical processes mediating their antineoplastic activity.     

Temporary and lasting cardiac effects of pre- and postnatal exposure to carbon monoxide

Pregnant female rats inhaled 200 ppm CO for the last 18 days of gestation, and a portion of their young inhaled 500 ppm CO for an additional 29 days after birth. Body weight (BW) and litter size of the CO-exposed newborn were significantly lower than those of unexposed controls. Heart weight (HW) of the exposed newborn was significantly larger than the controls, as was also $\text{HW}\text{BW}$ ratio. Hemoglobin concentration, hematocrit, and red blood cell count were significantly lower in the exposed newborn than in controls In young rats exposed to CO both pre- and postnatally, $\text{HW}\text{BW}$ ratio was more than twice as large as that of unexposed controls at 14, 21, and 29 days after birth (statistically significant), while in young rats exposed only as fetuses $\text{HW}\text{BW}$ ratio was only slightly higher than in controls at the same time intervals. The remaining rats in all three groups were allowed to mature to 105 days of age in room air, at which time they too were sacrificed. $\text{HW}\text{BW}$ ratio of the pre- and postnatally exposed rats was significantly elevated above the same parameters for the controls and rats exposed to CO as fetuses only. The $\text{HW}\text{BW}$ ratio of the latter two groups did not differ significantly from one another. Analysis of HW data using multiple exponential regression equations relating HW to BW, showed HW of the rats exposed to CO both pre- and postnatally to be 22% larger than predicted. The results suggest that fetal cardiomegaly induced by CO is entirely reversible, while neonatal exposure produces long-standing changes in HW.     

Antifungal and Antibacterial Activities of Endemic Pittocaulon. spp. from Mexico

Abstract

Extracts from Pittocaulon. spp. (Asteraceae) have been used in folk medicine to treat many ailments, particularly as anti-inflammatory and antimicrobial. Neither the bioactive components responsible nor the mechanisms involved have been evaluated. Here we report the antibacterial activities of their methanol and CH₂Cl₂ extracts and the effects on some fungal strains treated with CH₂Cl₂ extracts from root, stems, and flowers of P. praecox. (Cav.) H. Rob. & Brett., P. hintonii. H. Rob. & Brett., P. filare. (McVaugh) H. Rob. & Brett, P. velatum. (Greenm) H. Rob. & Brett., and P. bombycophole. (Bullock) H. Rob. & Brett. Thirteen extracts were obtained with MeOH and CH₂Cl₂ solvents from aerial parts and roots of five Pittocaulon. spp. for the first time in this species, and their antimicrobial activities were determined. The antimicrobial activities of these extracts were evaluated against the bacteria Staphylococcus aureus., Staphylococcus epidermidis., Bacillus subtilis., and Vibrio cholerae. (one El Tor strain, and a clinic case CDC-V12). Additionally, the CH₂Cl₂ extract was evaluated against Aspergillus niger., Fusarium moniliforme., Fusarium sporotrichum., Rizoctonia solanii., and Trichophyton mentagrophytes.. The most sensitive bacteria against these extracts were B. subtilis., S. epidermidis., and V. cholerae., a key bacterium in contaminated water. However, CH₂Cl₂ extracts from P. praecox., P. bombycophole., and P. hintonii. exhibited a significant antifungal activity against the fungal strains F. sporotrichum., R. solanii., and T. mentagrophytes.: at 1000 μg per disk, these extracts completely inhibited the mycelial growth of these fungi.