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There was no statistically significant difference in specific mouse skin carcinogenicity between smoke condensate from plain, flue-cured tobacco cigarettes with a normal tar to nicotine ratio and condensate from filter-tip cigarettes made from selected flue-cured tobaccos with a reduced tar to nicotine ratio.
Crude coal tar has been used in the treatment of dermatoses for many decades. In the last few years its use has been limited to skin diseases such as psoriasis and chronic dermatitis. Newer topical modalities for psoriasis are being used increasingly for treatment, but have failed to replace crude coal tar as a first-line treatment of psoriasis. We review the pharmacology, chemistry and use of crude coal in order to reappraise its role as a therapeutic agent in dermatology.
In the hope of reducing the adverse health consequences of smoking, physicians frequently advise their patients who cannot quit to smoke fewer cigarettes. Habitual smokers may compensate for the reduced number of cigarettes, however, by taking in more smoke per cigarette. We measured the intake of tar (estimated as mutagenic activity of the urine), nicotine, and carbon monoxide during short-term cigarette restriction. With a reduction from an average of 37 cigarettes to an average of 5 cigarettes per day, the intake of tobacco toxins per cigarette increased roughly threefold and daily exposure to tar and carbon monoxide declined only 50 percent. We conclude that smoking fewer cigarettes may reduce exposure to toxins and related adverse health consequences. However, consistent with a tendency to maintain intake of nicotine, the magnitude of the benefit is much less than expected. Whether "oversmoking" persists during long-term restriction of cigarettes requires further investigation.
AIMS: To assess the effect of maternal smoking and environmental tobacco smoke (ETS) on risk of small for gestational age infants (SGA). METHODS: Case-control study of 844 cases and 870 controls. RESULTS: Maternal smoking in pregnancy was associated with an increased risk of SGA (adjusted odds ratio (OR)= 2.41; 95% confidence interval (CI) = 1.78, 3.28). We could not detect an increased risk of SGA with paternal smoking, or with other household smokers when the mother was a non-smoker, but did find an increased risk with exposure to ETS in the workplace or while socializing. Infants of mothers who ceased smoking during pregnancy were not at increased risk of SGA, but those who decreased but did not stop remained at risk of SGA. There was no evidence that the concentration of nicotine and tar in the cigarettes influenced the risk of SGA. CONCLUSIONS: Maternal smoking in pregnancy is a major risk factor for SGA. This study suggests that mothers should be advised to cease smoking completely during pregnancy, and that a reduction in the number of cigarettes smoked or smoking low tar or nicotine concentration cigarettes does not reduce the risk of SGA.
This article will outline a pragmatic approach directed to incorporating key elements of a scientific review of the literature and derive a proposal for an occupational exposure standard for coal tar, coal tar pitch, creosote, petroleum pitch, bitumen and asphalt, six substances which contain polynuclear aromatic hydrocarbons. Five approaches to the standard setting process are reviewed and their strengths and weaknesses discussed. Unfortunately there does not exist an acceptable epidemiological data set, other than the coke oven emission studies, on which to base a valid and reliable risk assessment model. Based on comparative potency experiments of complex mixtures, consideration of the state-of-the-art sampling and analytical methods, prevention of acute human health effects, and current existing standards for these substances throughout the world, a set of recommended exposure standards are derived for health policy makers.
Cytochrome P4501A1 is known to be expressed in skin and thus has been implicated in the pathogenesis of skin cancer due to certain environmental carcinogens. Retinoic acid (RA) has been used in chemoprevention of certain skin and other epithelial cancers. Therefore, we used Northern and Western analysis to determine the effect of externally applied RA on basal P4501A1 expression. RA reduced basal levels of P4501A1 mRNA and protein by 68 (n = 14, P = 0.005) and 75% (n = 7, P = 0.04) respectively. RA application also reduced basal levels of P4501A2 (another P4501A1 subfamily member) mRNA by 93% (n = 7, P = 0.001) as determined by reverse transcription-polymerase chain reaction. Interestingly, P4501A1 mRNA expression induced by coal tar or glucocorticoid (clobetasol) was reduced 46 (n = 10, P = 0.003) and 69% (n = 5, P < 0.05) respectively by RA co-application. Downregulation of basal P4501A1 expression and antagonism of coal tar mediated P4501A1 induction by RA may be a mechanism involved in chemo-prevention of skin and other epithelial cancer by RA.
The skin of atopic dermatitis patients provides an excellent model to study the role of inflammation in benzo[a]pyrene (BaP) activation, since these individuals are often topically treated with ointments containing high concentrations of BaP. In this study we have determined, by HPLC with fluorescence detection, the BaP diol epoxide (BPDE)-DNA adduct levels in human skin after topical treatment with coal tar and their modulation by the -463G-->A myeloperoxidase (MPO) polymorphism, which reduces MPO mRNA expression. BPDE-DNA adduct levels were 2.2 and 14.2 adducts/10(8) nt for MPO-463AA/AG and -463GG, respectively. The predominant BaP tetrol observed was tetrol I-1, which is derived after hydrolysis of the anti-BPDE-DNA adduct. The tetrol I-1/II-2 ratio, corresponding to the anti/syn ratio, was 6.7. The (32)P-post-labeling assay was also performed and thin layer chromatograms showed a major spot with a chromatographic location corresponding to BPDE-DNA. The mean values of the BPDE-DNA adduct spots were 3.8 +/- 2.4 per 10(8) nt for MPO-463AA/AG (n = 3) and 18.4 +/- 11.0 per 10(8) nt for MPO-463GG (n = 7), respectively (P = 0.03). One individual with the homozygous mutant genotype (-463AA) even had a 13-fold lower adduct level (1.4 per 10(8) nt) as compared to MPO-463GG subjects. In conclusion, these data show for the first time: (i) the in vivo formation of BPDE-DNA adducts in human skin treated with coal tar; (ii) that the MPO-463AA/AG genotype reduced BPDE-DNA adduct levels in human skin.
Human exposure to polycyclic aromatic hydrocarbons (PAH) occurs through complex mixtures such as coal tar. The effect of complex PAH mixtures on the activation of carcinogenic PAH to DNA-binding derivatives and carcinogenesis were investigated in mice treated topically with NIST (National Institute of Standards and Technology) Standard Reference Material 1597 (SRM), a complex mixture of PAH extracted from coal tar, and either additional benzo[a]pyrene (B[a]P) or dibenzo[a,l]pyrene (DB[a,l]P). In an initiation-promotion study using 12-O-tetradecanoylphorbol-13-acetate as the promoter for 25 weeks, the SRM and B[a]P co-treated mice had a similar incidence of papillomas per mouse compared with the group exposed to B[a]P alone as the initiator. PAH-DNA adduct analysis of epidermal DNA by 33P-post-labeling and reversed-phase high-performance liquid chromatography found the SRM co-treatment led to a significant decrease in the total level of DNA adducts and B[a]P-DNA adducts to less than that observed in mice treated with B[a]P alone at 6, 12 and 72 h exposure. After 24 and 48 h exposure, there was no significant difference in the levels of adducts between these groups. In the DB[a,l]P initiation-promotion study, the co-treated group had significantly fewer papillomas per mouse than mice treated with DB[a,l]P alone as initiator. Averaging over the times of exposure gave strong evidence that mice co-treated with SRM and DB[a,l]P had a significantly lower level of PAH-DNA adducts than mice treated with DB[a,l]P alone. Western immunoblots showed that both cytochrome P450 (CYP) 1A1 and 1B1 were induced by the SRM. These results are consistent with the hypothesis that two major factors determining the carcinogenic activity of PAH within a complex mixture are (i) the persistence of certain PAH-DNA adducts as well as total adduct levels, and (ii) the ability of the components present in the mixture to inhibit the activation of carcinogenic PAH by the induced CYP enzymes.
A high performance liquid chromatography-electrochemical detection (HPLC-ECD) method was used for the highly sensitive and simultaneous determination of free cannabinoids and cannabinoic acids without derivatization. The HPLC-ECD method was linear from 5 to 500 ng/injection for all cannabinoids (THC, CBN, CBD, CBCh, THCA, CBDA, and CBChA). The detection limits of this method were 0.5 to 0.9 ng/injection for free cannabinoids and 1.2 to 2.5 ng/injection for cannabinoic acids at signal noise ratio of greater than 4. Cannabinoic contents in marijuana cigarettes and in tar and ash obtained by using an automatic smoking machine were measured by this method. Consequently, 62% of the sum of THC and THCA in the marijuana cigarette was converted to tar and 2.0% of that was left in the ash.
A threefold increase (P=0.006) in the number of skin tumors induced by beta irradiation was demonstrated in rats after surface applications of cigarette tar. The effect appeared due to a tumor-promoting activity of the cigarette tar rather than to an additive tumorigenic effect of the two agents.
In Pseudomonas putida strain G7, a LysR-type positive transcriptional activator protein encoded by nahR is necessary for activation of two operons involved in naphthalene catabolism [Schell, M. A. & Poser, E. F. (1989). J Bacteriol 171, 837-846]. The role of an nahR homologue, NCIB-nahR, in another naphthalene-metabolizing bacterium, P. putida NCIB 9816-4 was verified. Targeted disruption of NCIB-nahR by homologous recombination resulted in a growth defect in the presence of naphthalene or salicylate as sole carbon and energy source. The nahR homologues and intergenic regions between nahR-like and nahG-like genes from P. putida NCIB 9816-4 and seven bacteria native to a naphthalene-rich coal tar contaminated site were amplified by PCR using degenerate primers. The amplified nahR homologues and the intergenic regions were cloned and sequenced. Alignment of the deduced amino acid sequences from NahR homologues revealed that NahR-like proteins showed only minor variations in all investigated naphthalene-degrading isolates. The intergenic regions, together with known NahR-binding sites showed the consensus NahR-protein-binding sites (5'-ATTCACGCTN(2)TGAT-3'). Surprisingly, amplified intergenic regions from naphthalene-degrading micro-organisms native to this study site were 100% identical to that of the pDTG1 plasmid (an archetypal naphthalene-catabolic plasmid from Pseudomonas putida NCIB 9816-4), but the nahR coding regions were not. DNA representing the uncultured microbial community was extracted from six sediment samples with varying coal tar exposure histories. PCR amplification of nahR from sediment DNA was observed in contaminated samples, but in uncontaminated samples only following laboratory incubation with naphthalene. The sediment-derived PCR products were sequenced and also found to be almost identical to known nahR genes. Thus, the structure and function of nahR-nahG regulatory genes appear to be highly conserved.
Crude coal tar (CCT) and certain photoreactive ingredients of CCT are photosensitizing agents used in the treatment of skin diseases (psoriasis, atopic eczema, etc.). Limited information is available in elucidating the mode of action of CCT in clearing psoriasis or causing skin photosensitization reactions. The production of singlet oxygen (1O2) and superoxide radicals (O(2) or HO2), the formation of interstrand cross-links (ICL) in DNA, and the skin photosensitization reaction caused by CCT or the ingredients present in tar preparations have been examined. Both type I (oxygen-independent) and type II (sensitized reactions requiring molecular oxygen) reactions are induced by CCT. Our data show that CCT and some of the photoreactive ingredients present in CCT produce 1O2, O(2), and ICL in DNA upon exposure to UVA radiation. Based on the equivalent concentration, the efficiency of various agents to produce 1O2 was of the following order: hematoporphyrin greater than phenanthridine greater than acridine greater than methylene blue greater than CCT greater than fluoranthrene greater than anthracene greater than pyrene greater than 8-methoxypsoralen greater than anthralin greater than chloroquine greater than anthralin dimer. The O(2) formation with CCT and its ingredients was also of the same order except for anthracene which was found to be a strong producer of O(2). The therapeutic effectiveness of CCT appears to be due to: (a) its cytotoxic effects, and (b) the production of 1O2, O(2), and ICL by CCT and its photoreactive ingredients. The skin photosensitizing (smarting, edema, and erythema responses) and carcinogenic properties of CCT may also be related to the production of 1O2 and O(2) and the formation of ICL which appear to be responsible for inducing the damage to the DNA and cell membrane.
The possible percutaneous absorption of the mutagens from patients receiving crude coal tar (CCT) and ultraviolet light was investigated. Urine samples were collected from nonsmoking volunteers, smoking, and nonsmoking psoriatic patients. Patients were treated with 1% CCT U.S.P. or 1 to 10% CCT in petrolatum in the evening. The following morning, patients received coal tar baths and then ultraviolet light (mainly 290-320 nm, UVB). Nonpolar organics in urine samples were extracted by adsorption onto XAD-2 resin and the extracted organics assayed in the Ames Salmonella/Microsome test. TA98 was the most sensitive bacterial strain to detect mutagenicity. Except for smoking psoriatic patients, the addition of liver homogenate was necessary to see mutagenicity. No increase in the number of revertants was observed when B-glucuronidase was added to the assay. Of 14 patients studied 12 had at least one mutagenic urine sample. Typical values for nonsmoking psoriatics treated with CCT ranged from 42 to 496 his +/20 ml of urine after the subtraction of spontaneous his + counts (26 +/- 6). Two nonsmoking normal volunteers were found to excrete mutagenic urines. Smoking psoriatic patients ranged from 213 to 1,100 his +/20 ml urine. This study demonstrates the percutaneous absorption of mutagens from CCT and indicates that its effects may not be limited to the skin.
Topical treatment of hairless hamster skin with crude coal tar has been shown to induce epidermal thickening, an increased labelling index in the basal cell layer, an elevation in NADP-dependent glucose-6-phosphate dehydrogenase activity throughout the epidermis, an increased squame count, comedo formation, and atrophy of the sebaceous glands. Ultraviolet light fluorescence microscopy of sections of treated skin suggests that the hair follicle is an important route for skin penetration by coal tar.
In official assays of the tar and nicotine yields of 12 popular brands of cigarettes, smoking machines took fewer puffs, on the average, in 1974 than in 1969. The decline in puffs appears to have been a major cause of the reported reductions in tar and nicotine yields during this period.
Roofers working with coal-tar pitch develop burning eyes and conjunctivitis which they subjectively associate with sun exposure. A coal-tar pitch distillate instilled in the conjunctivae of rabbits produced minimal or mild irritation in the absence of ultraviolet radiation, but irradiation with long-ultraviolet produced marked photophobia and severe keratoconjunctivitis.
Four hundred and twenty nine current smokers and ex-smokers who had provided details 12 years previously completed a self administered questionnaire about their present and past smoking habits, and two weeks later current smokers supplied an empty cigarette packet. The tar group and brand name of the current cigarette given on the questionnaire were compared with details on the packet, and the brand alleged to have been smoked 12 years ago was compared with that actually recorded at that time. Only 55% of "low middle" tar cigarettes as indicated by returned packets had been correctly identified in the questionnaire. The brand name was the same in the questionnaire and on the packet in 74% of cases. The recalled brand was confirmed by past records in only 49% of cases. It is concluded that current smokers should be asked to return an empty packet or packets of the cigarette brand or brands usually smoked with a self administered questionnaire and that follow up studies of populations for which brands of cigarette smoked were previously recorded might be more valid than studies relying on recall.
We developed a nonobtrusive technique to measure the volume puffed during smoking. An inductive plethysmographic coli placed around the cheeks was calibrated by coaching the subject to take graded puffs from an unlit cigarette connected in series to a 2-L Krogh spirometer. The device had a linear volume response that was unaltered by smoking filtered or unfiltered cigarettes or by the length of the cigarette. It remained calibrated after smoking 4 cigarettes over 150 min. Ten subjects smoked a high tar content (HTC) and a low tar content (LTC) cigarette, each with and without a cigarette holder. The mean puff volume from LTC of 52 +/- 15 ml was significantly higher than HTC of 39 +/- 10 ml (p less than 0.001). The number of puffs per cigarette (8.4 +/- 2.1 for LTC, 8.3 +/- 2.0 for HTC), the volume of inhaled (841 +/- 517 ml for LTC and 748 +/- 323 ml for HTC), and the duration of inhalation and associated breathhold (5.5 +/- 2.6 s for LTC and 5.6 +/- 2.4 s for HTC) as measured by respiratory inductive plethysmography were comparable. The perception of intensity of inhalation by the subjects bore little relationship to the objective measurement. A cigarette holder increased the number of puffs per cigarette to 12.6 +/- 4.8 for LTC (p less than 0.02) and to 11.9 +/- 3.6 for HTC (p less than 0.01 and increased the puff volume for HTC to 50 +/- 12 ml (p less than 0.01) and the duration of inhalation to 6.6 +/- 2.5 s for LTC (p less than 0.005). These results show that (1) smokers switched acutely from HTC to LTC draw larger puffs from LTC thereby possibly circumventing the perceived benefits of smoking LTC, (2) cigarette holders modify smoking pattern and hence if used with an incorporated flowmeter to monitor the natural pattern of smoking might give spurious information.