Bioequivalence Assessment of Two Dapoxetine Hydrochloride Formulations in Healthy Chinese Males Under Fasted and Fed Conditions.

This study evaluated the bioequivalence of the newly developed dapoxetine hydrochloride tablet relative to the marketed reference product by comparing their pharmacokinetic profiles under fasted and fed conditions. A total of 60 healthy Chinese male subjects participated in a single-center, 2-period, 2-sequence, randomized, open-label, self-crossover study with a washout period of 14 days, 30 in the fasted group and 30 in the fed group. Following a single 30-mg oral dose of the test or reference dapoxetine formulation, blood samples were collected before dosing to 72 hours after dosing. Liquid chromatography-tandem mass spectrometry was performed to measure plasma concentration of dapoxetine and determine pharmacokinetic parameters through noncompartmental analysis. The vital signs and adverse events were also monitored during the study. The 90% confidence intervals of the geometric mean ratios for maximum plasma concentration, area under the plasma concentration-time curve from time 0 to the last concentration time, and area under the plasma concentration-time curve from time 0 extrapolated to infinity of the 2 dapoxetine formulations completely fell within the regulatory criteria for bioequivalence of 80%-125%. In addition, both dapoxetine hydrochloride formulations were generally well tolerated. The generic dapoxetine hydrochloride tablet was bioequivalent to the marketed reference product in healthy Chinese men with no discernible safety differences.

Comparative assessment of the effects of bumped kinase inhibitors on early zebrafish embryo development and pregnancy in mice.

Bumped kinase inhibitors (BKIs) are effective against a variety of apicomplexan parasites. Fifteen BKIs with promising in vitro efficacy against Neospora caninum tachyzoites, low cytotoxicity in mammalian cells, and no toxic effects in non-pregnant BALB/c mice were assessed in pregnant mice. Drugs were emulsified in corn oil and were applied by gavage for 5 days. Five BKIs did not affect pregnancy, five BKIs exhibited ~15-35% neonatal mortality and five compounds caused strong effects (infertility, abortion, stillbirth and pup mortality). Additionally, the impact of these compounds on zebrafish (Danio rerio) embryo development was assessed by exposing freshly fertilised eggs to 0.2-50 µM of BKIs and microscopic monitoring of embryo development in a blinded manner for 4 days. We propose an algorithm that includes quantification of malformations and embryo deaths, and established a scoring system that allows the calculation of an impact score (Si) indicating at which concentrations BKIs visibly affect zebrafish embryo development. Comparison of the two models showed that for nine compounds no clear correlation between Si and pregnancy outcome was observed. However, the three BKIs affecting zebrafish embryos only at high concentrations (≥40 µM) did not impair mouse pregnancy at all, and the three compounds that inhibited zebrafish embryo development already at 0.2 µM showed detrimental effects in the pregnancy model. Thus, the zebrafish embryo development test has limited predictive value to foresee pregnancy outcome in BKI-treated mice. We conclude that maternal health-related factors such as cardiovascular, pharmacokinetic and/or bioavailability properties also contribute to BKI-pregnancy effects.

Incorporating ToxCast™ data into naphthalene human health risk assessment.

Chronic inhalation of naphthalene causes nasal olfactory epithelial tumors in rats and benign lung adenomas in mice. The available human data do not establish an association between naphthalene and increased respiratory cancer risk. Therefore, cancer risk assessment of naphthalene in humans depends predominantly on experimental evidence from rodents. The United States Environmental Protection Agency's (US EPA) Toxicity Forecaster (ToxCast™) database contains data from 710 in vitro assays for naphthalene, the majority of which were conducted in human cells. Of these assays, only 18 were active for naphthalene, and all were in human liver cells. No assays were active in human bronchial epithelial cells. In our analysis, all of the active naphthalene ToxCast assay data were reviewed and used to: 1) determine naphthalene human inhalation concentrations corresponding to relevant activity concentrations for all active naphthalene assays, using a physiologically based pharmacokinetic (PBPK) model; and 2) evaluate the transcriptional responses for active assays in the context of consistency with the larger naphthalene data set and proposed modes of action (MoAs) for naphthalene toxicity and carcinogenicity. The transcriptional responses in liver cells largely reflect cellular activities related to oxidative stress and chronic inflammation. Overall, the results from our analysis of the active ToxCast assays for naphthalene are consistent with conclusions from our earlier weight-of-evidence evaluation for naphthalene carcinogenesis.

Mitigation of Rheumatic Arthritis in a Rat Model via Transdermal Delivery of Dapoxetine HCl Amalgamated as a Nanoplatform: In vitro and in vivo Assessment.

PURPOSE: Dapoxetine HCl (DH), a selective serotonin reuptake inhibitor, may be useful for the treatment of rheumatic arthritis (RA). The purpose of this study was to investigate the therapeutic efficacy of transdermal delivery of DH in transethosome nanovesicles (TENVs). This novel delivery of DH may overcome the drawbacks associated with orally administered DH and improve patient compliance. METHODS: DH-TENV formulations were prepared using an injection- sonication method and optimized using a 33 Box-Behnken-design with Design Expert® software. The TENV formulations were assessed for entrapment efficiency (EE-%), vesicle size, zeta potential, in vitro DH release, and skin permeation. The tolerability of the optimized DH-TENV gel was investigated using a rat skin irritation test. A pharmacokinetic analysis of the optimized DH-TENV gel was also conducted in rats. Moreover, the anti-RA activity of the optimized DH-TENV gel was assessed based on the RA-specific marker anti-cyclic cirtullinated peptide antibody (anti-CCP), the cartilage destruction marker cartilage oligomeric matrix protein (COMP) and the inflammatory marker interleukin-6 (IL-6). Level of tissue receptor activator of nuclear factor kappa-Β ligand (RANKL) were also assessed. RESULTS: The optimized DH-TENV formulation involved spherical nanovesicles that had an appropriate EE- % and skin permeation characteristic. The DH-TENV gel was well tolerated by rats. The pharmacokinetics analysis showed that the optimized DH-TENV gel boosted the bioavailability of the DH by 2.42- and 4.16-fold compared to the oral DH solution and the control DH gel, respectively. Moreover, it significantly reduced the serum anti-CCP, COMP and IL-6 levels and decreased the RANKL levels. Furthermore, the DH-TENV gel attenuated histopathological changes by almost normalizing the articular surface and synovial fluid. CONCLUSION: The results indicate that DH-TENVs can improve transdermal delivery of DH and thereby alleviate RA.

Phototoxic risk assessment of dermally-applied chemicals with structural variety based on photoreactivity and skin deposition.

Combined use of photochemical and pharmacokinetic (PK) data for phototoxic risk assessment was previously proposed, and the system provided reliable phototoxic risk predictions of chemicals in same chemical series. This study aimed to verify the feasibility of the screening system for phototoxic risk assessment on dermally-applied chemicals with wide structural diversity, as a first attempt. Photochemical properties of test chemicals, 2-acetonaphthalene, 4'-methylbenzylidene camphor, 6-methylcoumarin, methyl N-methylanthranilate, and sulisobenzone, were evaluated in terms of UV absorption and reactive oxygen species (ROS) generation, and PK profiles of the test chemicals in rat skin were characterized after dermal co-application. All test chemicals showed strong UVA/B absorption with molar extinction coefficients of over 3000 M-1⋅cm-1, and irradiated 2-acetonaphthalene, 6-methylcoumarin, and methyl N-methylanthranilate exhibited significant ROS generation. Dermally-applied 2-acetonaphthalene and 4'-methylbenzylidene camphor indicated high and long-lasting skin deposition compared with the other test chemicals. Based on the photochemical and PK data, 2-acetonaphthalene was predicted to have potent phototoxic risk. The predicted phototoxic risk of the test chemicals by integration of obtained data was mostly consistent with their in vivo phototoxicity observed in rat skin. The screening strategy employing photochemical and PK data would have high prediction capacity and wide applicability for photosafety evaluation of chemicals.

Assessment of CYP-Mediated Drug Interactions for Evocalcet, a New Calcimimetic Agent, Based on In Vitro Investigations and a Cocktail Study in Humans.

Evocalcet is a novel calcimimetic agent for the treatment of secondary hyperparathyroidism (SHPT). This study evaluated the effects of evocalcet on inhibition and induction of cytochrome P450 (CYP) isozymes. Although drug interactions arising from reversible inhibition of CYP isozymes by evocalcet were considered unlikely based on the results of in vitro studies and static model analyses, the potential for evocalcet to cause time-dependent inhibition of CYP3A or induction of several CYP isozymes could not be ruled out. Therefore, a clinical drug-drug interaction (DDI) study to evaluate the effects of evocalcet on the pharmacokinetics (PKs) of probe substrates for CYP isozymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, and CYP3A) was conducted in healthy male volunteers using a novel cocktail combination. Evocalcet did not significantly affect the PKs of the probe substrates, confirming that CYP-mediated interactions were unlikely.

Hypothesis-based weight-of-evidence evaluation and risk assessment for naphthalene carcinogenesis.

Inhalation of naphthalene causes olfactory epithelial nasal tumors in rats (but not in mice) and benign lung adenomas in mice (but not in rats). The limited available human data have not identified an association between naphthalene exposure and increased respiratory cancer risk. Assessing naphthalene's carcinogenicity in humans, therefore, depends entirely on experimental evidence from rodents. We evaluated the respiratory carcinogenicity of naphthalene in rodents, and its potential relevance to humans, using our Hypothesis-Based Weight-of-Evidence (HBWoE) approach. We systematically and comparatively reviewed data relevant to key elements in the hypothesized modes of action (MoA) to determine which is best supported by the available data, allowing all of the data from each realm of investigation to inform interpretation of one another. Our analysis supports a mechanism that involves initial metabolism of naphthalene to the epoxide, followed by GSH depletion, cytotoxicity, chronic inflammation, regenerative hyperplasia, and tumor formation, with possible weak genotoxicity from downstream metabolites occurring only at high cytotoxic doses, strongly supporting a non-mutagenic threshold MoA in the rat nose. We also conducted a dose-response analysis, based on the likely MoA, which suggests that the rat nasal MoA is not relevant in human respiratory tissues at typical environmental exposures. Our analysis illustrates how a thorough WoE evaluation can be used to support a MoA, even when a mechanism of action cannot be fully elucidated. A non-mutagenic threshold MoA for naphthalene-induced rat nasal tumors should be considered as a basis to determine human relevance and to guide regulatory and risk-management decisions.

Preclinical assessment of Orteronel(®), a CYP17A1 enzyme inhibitor in rats.

Orteronel (TAK-700) is a novel and selective inhibitor of CYP17A1, which is expressed in testicular, adrenal and prostate tumor tissues. Orteronel is currently in Phase-III clinical development for metastatic castration-resistant prostate patients. The objective of the study is to assess the permeability, metabolic stability (in various preclinical and human liver microsomes), identify the major CYPs involved in the metabolism of Orteronel. We have also studied the pharmacokinetics and excretion of Orteronel in Sprague-Dawley rats. Orteronel was found to be stable in various liver microsomes tested. The half-life (t ½) of Orteronel with intravenous (i.v.) route was found to be 1.65 ± 0.22 h. The clearance and volume of distribution by i.v. route for Orteronel were found to be 27.5 ± 3.09 mL/min/kg and 3.94 ± 0.85 L/kg, respectively. The absorption of Orteronel was rapid, with maximum concentrations of drug in plasma of 614 ± 76.4, 1,764 ± 166, 4,652 ± 300 and 17,518 ± 3,178 ng/mL attained at 0.38, 0.75, 0.50 and 0.83 h, respectively, after oral administration of Orteronel at 5, 10, 30 and 100 mg/kg as a suspension. In the dose proportional oral pharmacokinetic study, the mean t ½ by oral route was found to be ~3.5 h and bioavailability ranged between 69 and 89 %. The primary route of elimination for Orteronel is urine.

Assessment of cytochrome P450-mediated drug-drug interaction potential of orteronel and exposure changes in patients with renal impairment using physiologically based pharmacokinetic modeling and simulation.

Orteronel is a nonsteroidal, selective inhibitor of 17,20-lyase that was recently in phase 3 clinical development as a treatment for castration-resistant prostate cancer. In humans, the primary clearance route for orteronel is renal excretion. Human liver microsomal studies indicated that orteronel weakly inhibits CYP1A2, 2C8, 2C9 and 2C19, with IC50 values of 17.8, 27.7, 30.8 and 38.8 µm, respectively, whereas orteronel does not inhibit CYP2B6, 2D6 or 3A4/5 (IC50 > 100 µm). Orteronel also does not exhibit time-dependent inhibition of CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 or 3A4/5. The results of a static model indicated an [I]/Ki ratio >0.1 for CYP1A2, 2C8, 2C9 and 2C19. Therefore, a physiologically based pharmacokinetic (PBPK) model was developed to assess the potential for drug-drug interactions (DDIs) between orteronel and theophylline, repaglinide, (S)-warfarin and omeprazole, which are sensitive substrates of CYP1A2, 2C8, 2C9 and 2C19, respectively. Simulation of the area under the plasma concentration-time curve (AUC) of these four CYP substrates in the presence and absence of orteronel revealed geometric mean AUC ratios <1.25. Therefore, in accordance with the 2012 US FDA Draft Guidance on DDIs, orteronel can be labeled a 'non-inhibitor' and further clinical DDI evaluation is not required. In PBPK models of moderate and severe renal impairment, the AUC of orteronel was predicted to increase by 52% and 83%, respectively. These results are in agreement with those of a clinical trial in which AUC increases of 38% and 87% were observed in patients with moderate and severe renal impairment, respectively.

Assessment of oral toxicity and safety of 9-cis-UAB30, a potential chemopreventive agent, in rat and dog studies.

9-cis-UAB30 is a potential chemopreventative agent that has been shown to be effective on many different types of tumors. The safety and toxicity of 9-cis-UAB30 had not been previously established. These studies were conducted to evaluate the potential toxicity and pharmacokinetics in a rodent and a nonrodent species for the purpose of investigational new drug submission. Oral gavage administration of 9-cis-UAB30 at the doses 0, 3, 15, and 100 mg/kg/day to CD® rats for 28 days showed a dose-dependent (although not dose-proportional) increase in plasma drug levels in week 4. The liver was the target organ for toxicity of 9-cis-UAB30. Hepatomegaly along with increases in serum aspartate-aminotransferase and alkaline-phosphatase levels were seen in rats. Moderate hypoalbuminemia and hyperglobulinemia resulted in a decreased albumin/globulin ratio. Histopathology revealed hepatocellular change consistent with hepatic glycogen deposition. Toxicity studies in dogs did not show treatment-related toxicity at doses as high as 100 mg/kg/day (highest dose tested) administered by capsules for 28 days. No effects on the central nervous system (functional observational battery in rats) or cardiovascular function (safety pharmacology study in telemeterized dogs) were seen. The no observed adverse effect level (NOAEL) in the rat studies was 3 mg/kg/day; however, the adverse effects seen in rats receiving 15 mg/kg/day (the least observed adverse effect level) was a slight, but statistically significant, elevation in fibrinogen and decrease in prothrombin time, which may be a sign of some tendency for increased blood coagulation. The NOAEL in the dog study was at least 100 mg/kg/day.

Assessment of biomarkers of drug-induced kidney injury in cynomolgus monkeys treated with a triple reuptake inhibitor.

Drug-induced kidney injury (DIKI) results in attrition during drug development; new DIKI urinary biomarkers offer potential to detect and monitor DIKI progression and regression, but frequently only in rats. The triple reuptake inhibitor (TRI) PRC200-SS represents a new class of antidepressants that elevate synaptic levels of serotonin, norepinephrine, and dopamine and is expected to produce more rapid onset and better antidepressant efficacy than single or dual inhibitors. Although preclinical studies and recent clinical trials lend support to this concept of superior efficacy for TRIs, there is little information on the safety profile of this class of compounds. Using histopathology and DIKI biomarkers, in single- and repeat dose toxicological studies in cynomolgus monkeys, PRC200-SS demonstrated dose-proportional kidney toxicity. Characterization of the histopathological lesions, using a combination of immunohistochemistry (IHC) and urinary biomarker analysis, indicated that the compound is a distal tubule and collecting duct toxicant. Segment specificity for the lesions was shown using a newly developed triple IHC combination method with antibodies against calbindin D28, aquaporin 2, and aquaporin 1. Urinary biomarker analyses, using multiplex immunoassays, confirmed a dose-proportional increase in the excretion of calbindin D28 and clusterin in compound-treated monkeys with levels returning to baseline during the drug-free recovery period. These results constitute the validation of distal nephron DIKI biomarkers in the cynomolgus monkey and demonstrate the utility of calbindin D28 and clusterin to monitor the progression of distal nephron DIKI, representing potential early biomarkers of DIKI for the clinic.

Assessment of basic indirect pharmacodynamic response models with physiological limits.

Many physiological factors are regulated by homeostatic mechanisms to maintain normal body function. Empirical lower Rl (Model I and IV) or upper Rh limits (Model II and III) were included in current basic indirect response (IDR) models to account for the additional role of physiological limits (IDRPL). Various characteristics of these models were evaluated with simulations and explicit equations. The simulations reveal that the expanded models exhibit most properties of basic indirect response models, such as slow response initiation, lag time between the kinetic and dynamic peaks, a large dose plateau, and shift in Tmax with dose. The proposed models always produce lesser net responses than predicted by basic IDR models. Simulations demonstrate that addition of a parameter limit which is close to the baseline has a great influence on the overall and maximum responses and fitted model parameters. Only stimulatory IDRPL Models III and IV allow resolution of all model parameters in the absence of clear indications or predetermined values of the lower or upper limits. However, all four models are able to resolve model parameters when subgroups with different baselines are simultaneously fitted. These models create new interpretations of the determinants of baseline conditions which can be important in assessing inter-subject variability in responses. The applicability of IDRPL models is demonstrated using several examples from the published literature. Indirect response models with physiological limits will be useful in characterizing drug responses for turnover systems which are maintained within a certain range.

Terbinafine: a review of its use in onychomycosis in adults.

UNLABELLED: Terbinafine, an orally and topically active antimycotic agent, inhibits the biosynthesis of the principal sterol in fungi, ergosterol, at the level of squalene epoxidase. Squalene epoxidase inhibition results in ergosterol-depleted fungal cell membranes (fungistatic effect) and the toxic accumulation of intracellular squalene (fungicidal effect). Terbinafine has demonstrated excellent fungicidal activity against the dermatophytes and variable activity against yeasts and non-dermatophyte molds in vitro. Following oral administration, terbinafine is rapidly absorbed and widely distributed to body tissues including the poorly perfused nail matrix. Nail terbinafine concentrations are detected within 1 week after starting therapy and persist for at least 30 weeks after the completion of treatment. Randomized, double-blind trials showed oral terbinafine 250 mg/day for 12 or 16 weeks was more efficacious than itraconazole, fluconazole and griseofulvin in dermatophyte onychomycosis of the toenails. In particular, at 72 weeks' follow-up, the multicenter, multinational, L.I.ON. (Lamisil vs Itraconazole in ONychomycosis) study found that mycologic cure rates (76 vs 38% of patients after 12 weeks' treatment; 81 vs 49% of recipients after 16 weeks' therapy) and complete cure rates were approximately twice as high after terbinafine treatment than after itraconazole (3 or 4 cycles of 400 mg/day for 1 week repeated every 4 weeks) in patients with toenail mycosis. Furthermore, the L.I.ON. Icelandic Extension study demonstrated that terbinafine was more clinically effective than intermittent itraconazole to a statistically significant extent at 5-year follow-up. Terbinafine produced a superior complete cure rate (35 vs 14%), mycologic cure rate (46 vs 13%) and clinical cure rate (42 vs 18%) to that of itraconazole. The mycologic and clinical relapse rates were 23% and 21% in the terbinafine group, respectively, compared with 53% and 48% in the itraconazole group. In comparative clinical trials, oral terbinafine had a better tolerability profile than griseofulvin and a comparable profile to that of itraconazole or fluconazole. Post marketing surveillance confirmed terbinafine's good tolerability profile. Adverse events were experienced by 10.5% of terbinafine recipients, with gastrointestinal complaints being the most common. Unlike the azoles, terbinafine has a low potential for drug-drug interactions. Most pharmacoeconomic evaluations have shown that the greater clinical effectiveness of oral terbinafine in dermatophyte onychomycosis translates into a cost-effectiveness ratio superior to that of itraconazole, fluconazole and griseofulvin. CONCLUSION: Oral terbinafine has demonstrated greater effectiveness than itraconazole, fluconazole and griseofulvin in randomized trials involving patients with onychomycosis caused by dermatophytes. The drug is generally well tolerated and has a low potential for drug interactions. Therefore, terbinafine is the treatment of choice for dermatophyte onychomycosis.

In vivo assessment of enhanced topical delivery of terbinafine to human stratum corneum.

PURPOSE: The objective of this study was to evaluate, using attenuated total reflectance Fourier transform infrared spectroscopy, the stratum corneum (SC) bioavailability of terbinafine (TBF) following topical treatment with four different formulations. METHODS: Four skin sites on the ventral forearms of five healthy volunteers were treated for 2 h using one of four formulations based on a vehicle consisting of 50% ethanol and 50% isopropyl myristate. Three of these formulations included a percutaneous penetration enhancer: either 5% oleic acid, 10% 2-pyrrolidone or 1% urea. The SC concentration profile of TBF was measured by repeated infrared spectroscopic measurements while sequentially stripping off the layers of this barrier membrane with adhesive tape. This method was validated by HPLC analysis of TBF extracted from the stripped tapes. Transepidermal water loss (TEWL) measurements were also performed, to permit facile estimation of SC thickness. RESULTS: The SC concentration profiles of TBF were fitted to the appropriate solution of Fick's second law of diffusion, thereby allowing determination of the characteristic diffusion and partitioning parameters of the permeating drug. This analysis enabled the efficacies of the different formulations tested to be compared to the no-enhancer control. While it was found that the formulation containing 5% oleic acid significantly enhanced the SC availability of TBF, the other formulations did not improve the apparent drug delivery. CONCLUSIONS: A facile and minimally invasive methodology to evaluate an important aspect of topical drug bioavailability has been described. The analytical methods used (infrared spectroscopy and HPLC) allow estimates of both relative and absolute drug bioavailability in the SC and may be useful, therefore, in the critical determination of bioequivalence between topical formulations.

The evolving role of itraconazole, fluconazole and terbinafine in the treatment of tinea capitis.

Tinea capitis has become an increasing public health concern in the last decade. The increased incidence of the disease; its sometimes subtle, nonspecific clinical presentation; and the development of tolerance to griseofulvin therapy have led to the need for alternative safe, efficacious, inexpensive therapies that work rapidly. Itraconazole, fluconazole and terbinafine all possess pharmacologic and pharmacokinetic characteristics that theoretically would make them ideal therapies for tinea capitis. However, few randomized double blind controlled studies using these agents have been published. Thus far none have been conducted in the United States. The best available data support the utility and safety of the new antifungals in the treatment of tinea capitis. However, one must keep in mind that they are not yet approved by the Food and Drug Administration for this indication. Safety and cost considerations favor terbinafine for the treatment of T. tonsurans infections. M. canis infections may respond better to itraconazole, but good controlled studies to confirm this speculation have not been conducted. Short course and pulse dosing are particularly exciting options that may decrease cost and lower the risk of adverse side effects. Further useful information will hopefully come from future randomized double blind studies that will include patients from the United States. Studies using standardized definitions of disease, cure and appropriate follow-up evaluation of clinical and mycologic cure will best identify the optimal therapy for pediatric tinea capitis infections. The new systemic antifungals may provide more therapeutic options for fungal infections of the scalp. Note added in proof A recent trial comparing short course terbinafine and intraconazole therapy demonstrated that 2-week therapy with either drug provided good results and high cure rates (Jahangir M, et al. Br J Dermatol 1998;139:672-4).

Environmental risk assessment for the polycyclic musks AHTN and HHCB in the EU. I. Fate and exposure assessment.

For the environmental exposure assessment of the fragrance ingredients 7-acetyl-1,1,3,4,4,6-hexamethyl-1,2,3,4-tetrahydronaphthalene (AHTN) and 1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexamethylcyclopenta-gamma-2-ben zopyran (HHCB) the following properties were determined: vapour pressure 0.0682 and 0.0727 Pa; water solubility 1.25 and 1.75 mg/l; log K(ow) 5.7 and 5.9; log K(oc) 4.80 and 4.86; bioconcentration factor in fish: 597 and 1584 (fresh weight) for AHTN and HHCB, respectively. Both substances are degraded to more polar metabolites in fish, in soil and during sewage treatment. A review is made of concentrations measured in sludge, in freshwater and marine systems including suspended matter, sediment and fish. The 90th-percentile in more than 200 surface water samples is 0.3 microg/l for AHTN and 0.5 microg/l for HHCB. The 90th-percentile of the concentrations in fish is 0.12 mg/kg fresh weight for both substances (n = 27). These concentrations are lower by a factor of 5-15 than predicted on the basis of the yearly use volumes in Europe, 585 tonnes for AHTN and 1482 tonnes for HHCB. Concentrations in sludge-amended soils and in earthworms are predicted based on concentrations measured in sludge. For AHTN, the predicted values are: PECsoil, 0.029 mg/kg and PECworm, 0.065 mg/kg while for HHCB the corresponding figures are 0.032 and 0.099 mg/kg. These concentrations assume a biodegradation half-life in the soil of 180 days based on preliminary soil biodegradation data.

Urinary 1-naphthol excretion in the assessment of exposure to creosote in an impregnation facility.

OBJECTIVES: This study explored the possibility of using urinary 1-naphthol excretion as a marker of complex exposure among workers handling creosote. METHODS: Urine specimens of 6 workers from a creosote impregnation plant, where railroad ties were impreganted with coal tar creosote, were collected during 1 workweek, and the concentration of 1-naphthol was determined. 1-Naphthol in spot urine samples of 5 occupationally nonexposed male smokers was used as the background reference. Concurrently, naphthalene and 10 different polycyclic aromatic hydrocarbons (PAH) were determined in personal air samples. RESULTS: The mean airborne exposure of the workers was 1.5 mg/m3 for vaporous naphthalene, 5.9 micrograms/m3 for particulate PAH and 1.4 micrograms/m3 for PAH with 4-6 aromatic rings. The mean urinary concentration of 1-naphthol at the end of the workshift was 20.5 (range 3.5-62.1) mumol/l, whereas the referents' urinary concentration was below the detection limit (0.07 mumol/l). Airborne naphthalene correlated fairly well with 1-naphthol when measured at the end of the shift (r = 0.745). CONCLUSIONS: This method of analysis for 1-naphthol is sufficiently sensitive for measuring low occupational exposures to naphthalene. Low background exposures are, however, unlikely to result in detectable urinary levels of 1-naphthol. Since naphthalene is the most abundant compound in creosote vapor, urinary 1-naphthol determination serves well as a biological marker of exposure to vaporous creosote. Urinary 1-naphthol alone is not, however, a suitable marker for inhalatory or cutaneous exposure to PAH originating from creosote.