Efficacy of afoxolaner plus milbemycin oxime chewable tablets (NexGard Spectra®, Merial) against adult Ancylostoma ceylanicum hookworm, in dogs.

A fixed-combination chewable tablet incorporating afoxolaner plus milbemycin oxime (NexGard Spectra®, Merial) was tested in purpose-bred Beagle dogs for efficacy against adult Ancylostoma ceylanicum hookworms. Sixteen dogs were inoculated each by oral administration of approximately 500 infective larvae of A. ceylanicum. Seventeen days after inoculation, the dogs were weighed and allocated randomly to be treated with afoxolaner plus milbemycin oxime chewable tablets or to remain untreated. Commercial chewable tablets of different strength were combined to deliver doses as close as possible to the minimum effective dose of 2.5mg afoxolaner plus 0.5mg milbemycin oxime per kg body weight. Parasites were recovered and counted for determination of efficacy seven days after treatment. All eight dogs that had been left untreated were harboring adult A. ceylanicum (geometric mean, 317.8; range, 210-428) while only one and nine A. ceylanicum were recovered from two of the eight dogs treated with afoxolaner plus milbemycin oxime chewable tablets (geometric mean, 0.5; p<0.0001). Thus, 99.9% efficacy against induced infection of A. ceylanicum was obtained by the use of oral NexGard Spectra® at the minimum effective dose. Treatment with afoxolaner plus milbemycin oxime chewable tablets was well accepted and safe.

Efficacy of a novel topical combination of fipronil, (S)-methoprene, eprinomectin, and praziquantel, against the ticks, Ixodes ricinus and Ixodes scapularis, on cats.

Five controlled, blinded and randomized studies were conducted to examine the efficacy of a single topical application of a combination of fipronil, (S)-methoprene, eprinomectin, and praziquantel (BROADLINE(®), Merial) against induced infestations with Ixodes ticks on cats. Three studies investigated the efficacy against Ixodes ricinus and two against Ixodes scapularis. In each study, purpose-bred cats were assigned at random to an untreated group or to a treated group. For the studies using I. ricinus, cats were infested with 50 female ticks and a similar number of males 2 days before treatment application, and weekly afterwards on between four and six occasions. For the studies using I. scapularis, cats were infested with a total of 50 ticks (approximately 25 females and 25 males) according to the same schedule as for I. ricinus. Tick counts for the evaluation of efficacy were performed 48 h after treatment and 48 h after the subsequent weekly infestations. Weekly attachment rates to untreated cats of at least 29% for I. ricinus and at least 30% for I. scapularis demonstrated consistently that the ticks were vigorous and that the attachment rates were adequate for efficacy evaluation. In the I. ricinus studies, an efficacy of at least 93% was demonstrated for up to 37 days after the treatment. In the I. scapularis studies, the efficacy level was at least 95% 30 days after the treatment. The product was well tolerated and caused no adverse reaction.

Comparative acaricidal efficacy of the topically applied combinations fipronil/(S)-methoprene, permethrin/imidacloprid and metaflumizone/ amitraz against Dermacentor reticulatus, the European dog tick (ornate dog tick, Fabricius, 1794) in dogs.

The acaricidal efficacy against Dermacentor reticulatus in dogs of the commercial topical combinations fipronil/(S)-methoprene (FRONTLINE Combo spot-on dog), imidacloprid/permethrin (Advantix) and metaflumizone/amitraz (ProMeris Duo) was evaluated and compared. Three treatment groups and one untreated control group of six adult Beagle dogs each were randomly formed. Each treatment was administered topically once on Day-0, according to the recommended label dose and instructions for use. All dogs were infested weekly with approximately 50 adult unfed D. reticulatus over a period of seven weeks. Ticks were removed and counted approximately 48 hours after each infestation. The percent reduction in numbers of ticks for fipronil/(S)-methoprene was > or = 97% compared to untreated controls for all seven weekly infestations. The percent reductions for imidacloprid/permethrin and metaflumizone/amitraz were satisfactory initially but fell and stayed below 90 % after three weeks. From the third week onwards, fipronil/(S)-methoprene treated dogs had significantly fewer ticks than imidacloprid/permethrin or metaflumizone/amitraz treated dogs (p < 0.05).

A dynamic population-based model for the development of work-related respiratory health effects among bakery workers.

OBJECTIVES: This paper presents a dynamic population-based model for the development of sensitisation and respiratory symptoms in bakery workers. The model simulates a population of individual workers longitudinally and tracks the development of work-related sensitisation and respiratory symptoms in each worker. METHODS: The model has three components: a multi-stage disease model describing the development of sensitisation and respiratory symptoms in each worker over time; an exposure model describing occupational exposure to flour dust and allergens; and a basic population model describing the length of a worker's career in the bakery sector and the influx of new workers. Each worker's disease state is modelled independently using a discrete time Markov Chain, updated yearly using each individual's simulated exposure. A Bayesian analysis of data from a recent epidemiological study provided estimates of the yearly transition probabilities between disease states. RESULTS: For non-atopic/non-sensitised workers the estimated probabilities of developing moderate (upper respiratory) symptoms and progression to severe (lower respiratory) symptoms are 0.4% (95% CI 0.3 to 0.5%) and 1.1% (95% CI 0.6 to 1.9%) per mg/m(3)/year of flour dust, respectively, and approximately twice these for atopic workers. The model predicts that 36% (95% CI 26 to 46%) of workers with severe symptoms are sensitised to wheat and 22% (95% CI 12 to 37%) to alpha-amylase. The predicted mean latency period for respiratory symptoms was 10.3 years (95% CI 8.3 to 12.3). CONCLUSIONS: While the model provides a valuable population-level representation of the mechanisms contributing to respiratory diseases in bakers, it was primarily developed for use in quantitative health impact assessment. Future research will use the model to evaluate a range of workplace interventions, including achievable reductions in exposure and health surveillance. The general methodology is applicable to other diseases such as chronic obstructive pulmonary disease, silicosis and musculoskeletal disorders and could be particularly valuable for forecasting changes in long latency diseases.

Effect of an intervention aimed at reducing the risk of allergic respiratory disease in bakers: change in flour dust and fungal alpha-amylase levels.

INTRODUCTION: We evaluated the effect on exposure of an intervention programme, which focused on risk education and providing information on good work practices. This intervention programme was enrolled as part of a Dutch covenant in the flour processing industry (industrial bakeries, flour mills, ingredient producers). METHODS: Data from several measurement surveys collected pre- and post-intervention were used to evaluate changes in exposure over time. All datasets contained personal measurements analysed for flour dust and fungal alpha-amylase contents, and contextual information was available on process characteristics, work practice, and use of control measures. RESULTS: Changes in exposure over time varied substantially between sectors and jobs. For bakeries a modest downward annual trend of -2% was found for flour dust and -8% for amylase. For flour mills the annual trend for flour dust was -12%; no significant trend was observed for amylase. For ingredient producers results were generally non-significant but indicated a reduction in flour dust exposure and increase in fungal alpha-amylase exposure. Modest increase in use of control measures and proper work practices were reported in most sectors, especially the use of local exhaust ventilation and decreased use of compressed air. CONCLUSIONS: The magnitude of the observed reductions in exposure levels indicates that the sector-wide intervention strategy implemented during the covenant period had a limited overall effect. This indicates that a more rigorous approach is needed to substantially decrease the exposure levels to flour dust and related allergens and, respectively, the prevalence of associated occupational diseases.

REACH, non-testing approaches and the urgent need for a change in mind set.

The objectives of REACH cannot be achieved under the current risk assessment approach. A change in mind set among all the relevant stakeholders is needed: risk assessment should move away from a labor-intensive and animal-consuming approach to intelligent and pragmatic testing, by combining exposure and hazard data effectively and trying to group chemicals (category approaches). The focus should be on reducing the overall uncertainties of 30,000 chemicals while acknowledging the existence of the uncertainty paradox: reducing uncertainty in the assessment of individual chemicals following the classical chemical-by-chemical approach as we have in previous decades will result in a prolongation of uncertainty for the entire group of 30,000 chemicals as a whole. With the first REACH registration deadline (2010) rapidly approaching, a mind set change is urgently needed. We can speed up the regulatory acceptance process, starting with the maximum use of currently available exposure and hazard data, tools and models. Optimal use should also be made of experimental exposure and hazard data generated under REACH. Only such an approach will make it possible to obtain a sufficient level of information within the time frame of REACH. A much more intensive dialogue between stakeholders is necessary.

Occupational lung cancer risk among men in the Netherlands.

OBJECTIVES: To assess male lung cancer risks for industrial sectors in the Netherlands and to estimate the proportion of lung cancer attributed to working in specific industrial sectors. METHODS: Associations were studied among men aged 55-69 years (n = 58 279) from the prospective Netherlands Cohort Study. 1920 incident lung cancer cases were available after 11.3 years of follow-up. Based on a case-cohort design, and using Cox proportional hazards models, risks were estimated for blue collar workers in 26 industrial sectors. RESULTS: Adjustment for individual smoking habits affected risk estimates for some sectors, but adjustment for fruit/vegetables and alcohol intake did not. Adjusted for confounders, an increased risk of lung cancer was observed for employment for >/=15 years in blue collar jobs in the "electronics and optical instruments" industry (rate ratio (RR) 1.99; 95% CI 1.18 to 3.35), "construction and homebuilding business" (RR 1.64; 95% CI 1.21 to 2.22) and "railway company" (RR 2.40; 95% CI 1.00 to 5.73). The attributable fraction for working for >/=15 years in these three industries was 5%. In three other sectors there was a statistically non-significant elevated RR of >1.5. CONCLUSIONS: Male lung cancer risk is increased in several industrial sectors. Approximately 2000 lung cancer cases between 1986 and 1997 in the 55-69-year-old age group in the Netherlands may be attributable to working for >/=15 years in the three sectors with increased risk. In addition, estimates for occupational lung cancer risks for sectors may be biased if no individual information is available on smoking habits.

Dermal, inhalation, and internal exposure to 1,6-HDI and its oligomers in car body repair shop workers and industrial spray painters.

OBJECTIVES: To study inhalation and dermal exposure to hexamethylene diisocyanate (HDI) and its oligomers as well as personal protection equipment (PPE) use during task performance in conjunction with urinary hexamethylene diamine (HDA) in car body repair shop workers and industrial spray painters. METHODS: Personal task based inhalation samples (n = 95) were collected from six car body repair shops and five industrial painting companies using impingers with di-n-butylamine (DBA) in toluene. In parallel, dermal exposure was assessed using nitril rubber gloves. Gloves were submerged into DBA in toluene after sampling. Analysis for HDI and its oligomers was performed by LC-MS/MS. Urine samples were collected from 55 workers (n = 291) and analysed for HDA by GC-MS. RESULTS: Inhalation exposure was strongly associated with tasks during which aerosolisation occurs. Dermal exposure occurred during tasks that involve direct handling of paint. In car body repair shops associations were found between detectable dermal exposure and glove use (odds ratio (OR) 0.22, 95% confidence interval (CI) 0.09 to 0.57) and inhalation exposure level (OR 1.34, 95% CI 0.97 to 1.84 for a 10-fold increase). HDA in urine could be demonstrated in 36% and 10% of car body repair shop workers and industrial painting company workers respectively. In car body repair shops, the frequency of detectable HDA was significantly elevated at the end of the working day (OR 2.13, 95% CI 1.07 to 4.22 for 3-6 pm v 0-8 am). In both branches HDA was detected in urine of approximately 25% of the spray painters. In addition HDA was detected in urine of a large proportion of non-spray painters in car body repair shops. CONCLUSION: Although (spray) painting with lacquers containing isocyanate hardeners results in the highest external exposures to HDI and oligomers, workers that do not perform paint related tasks may also receive a considerable internal dose.

A probabilistic assessment of the impact of interventions on oncology nurses' exposure to antineoplastic agents.

OBJECTIVE: The main goal was to investigate the potential of a probabilistic approach for exposure assessment and use this information to evaluate the impact of a complex of policy actions/interventions on dermal exposure to antineoplastic agents among oncology nurses. The central theme of this study was to make optimal use of existing data, supplemented only with limited additional information from a questionnaire survey. METHODS: A task based exposure model was used to estimate dermal exposure of the hands among oncology nurses in non-academic hospitals in the Netherlands. Monte Carlo simulation was used to integrate information from available (exposure) studies and generate exposure distributions for the total population of oncology nurses in both pre- and post-intervention situation. Graphs and descriptive statistics of the simulated exposure distributions were used to evaluate trends in population exposure. RESULTS: The inventory showed that important intervention occurred in the preparation and administering of antineoplastic agents and in the handling of urine. Hardly any changes were identified in de nursing tasks. The use of gloves seemed to have decreased for a number of tasks. The results of the analysis show that the interventions did not affect the median exposure. However frequencies of occurrence of individuals with very high and very low total dermal exposures decreased substantially in the post-intervention situation. Analysis of the effect of pregnancy showed that pregnancy is very unlikely to influence exposure or any of the key input variables. CONCLUSIONS: The present study shows that the probabilistic approach adds valuable information to deterministic exposure assessment, especially when extrapolating data on a subpopulation to populations of individuals at large. The results show that the identified changes in the past decade in Dutch non-academic hospitals resulted in changes in the exposure distribution of antineoplastic agents among oncology nurses.

Paternal occupational exposures and embryo implantation rates after IVF.

OBJECTIVE: To investigate any influence of paternal occupational exposures on implantation rates after IVF. DESIGN: Cohort study of couples who sought IVF treatment. SETTING: University Hospital Utrecht, The Netherlands. PATIENT(S): The study population was composed of 726 couples pursuing IVF treatment. INTERVENTION(S): Only the earliest IVF treatment cycle with ET was selected for the analysis. All couples filled in a generic questionnaire on lifestyle factors and details about their occupation. In addition, more detailed exposure information was obtained for pesticides with use of job-specific questionnaires and a subsequent telephone interview. MAIN OUTCOME MEASURE(S): The implantation rate was defined as the number of gestational sacs seen with ultrasound at 6-7 weeks of pregnancy, divided by the number of embryos replaced. RESULT(S): A significantly reduced implantation rate was seen among couples with male partners working in occupations with presumably high levels of organic solvent exposure. Conversely, paternal pesticide exposure was significantly associated with an increased implantation rate. Paternal exposures to metal dust or fumes and welding fumes were not related to the probability of implantation. CONCLUSION(S): The findings suggested that paternal organic solvent exposure decreased the implantation rate among couples undergoing IVF-ET treatment.

Pesticide exposure and decreased fertilisation rates in vitro.

The effect of paternal occupational exposures on fertilising ability was investigated in 836 couples who sought in-vitro fertilisation treatment. Fertilisation rates were significantly decreased for couples with paternal pesticide exposure.

Assessment of occupational exposures in a general population: comparison of different methods.

OBJECTIVES: To evaluate the relative merits of job specific questionnaires and various alternative assessment methods of occupational exposures often used in general population studies. METHODS: Subjects were participants in a hospital based case-control study of risk factors for male infertility. Estimates of exposure to organic solvents and chromium, based on job specific questionnaires, generic questionnaires, self reports of exposure, an external job exposure matrix (JEM), and a population specific JEM were compared with passive diffuse dosimeter results and measurements in urine. Urine samples from the end of the shift were analysed for metabolites of toluene, xylene, several glycol ethers, trichloroethylene, and chromium. Passive dosimeter date, metabolites of specific solvents, and urinary chromium concentrations were available for 89, 267, and 156 subjects, respectively. The alternative methods and measurements in urine were compared by means of the Cohen's kappa statistic and by computing the positive predictive value, sensitivity, and specificity of the alternative methods against measurements in urine. RESULTS: Passive dosimeter results indicated that exposure classifications with job specific questionnaire information could discriminate between high and low exposures. The kappa coefficients were < 0.4, so agreement between the various methods and measurements in urine was poor. Sensitivity of the methods ranged from 0.21 to 0.85, whereas specificity ranged from 0.34 to 0.94. Positive predictive values ranged from 0.19 to 0.58, with the highest values for job specific questionnaires. CONCLUSIONS: The results indicate that the implementation of job specific questionnaires in a general population study might be worth the extra expense it entails, bearing in mind the paramount importance of avoiding false positive exposure estimates when exposure prevalence is low.

Occupationally related exposures and reduced semen quality: a case-control study.

OBJECTIVE: To determine whether there is an association between abnormal semen parameters and occupational exposures to organic solvents, metals, and pesticides. DESIGN: Case-control study using three case groups based on different cutoff values for semen parameters and one standard reference group. SETTING: University Hospital Utrecht and University Hospital Rotterdam, the Netherlands. PATIENT(S): Male partners of couples having their first consultation at the two infertility clinics (n = 899). INTERVENTION(S): Men provided at least one semen sample. Occupational exposure was assessed with use of job-specific questionnaires, a job exposure matrix, and measurements of metals and metabolites of solvents in urine. MAIN OUTCOME MEASURE(S): Standard clinical semen analyses were used to define case groups and controls. RESULT(S): An association between aromatic solvents and reduced semen quality was demonstrated, irrespective of the exposure assessment method used. The associations were stronger if the case definition was based on stricter cutoff values for semen parameters. Risk estimates were higher if the analysis was restricted to primary infertile men. Exposure to other pollutants at the workplace was not associated with impaired semen quality. CONCLUSION(S): The findings indicated an association between aromatic solvent exposure and impaired semen parameters.

Exposure to fungicides in fruit growing: re-entry time as a predictor for dermal exposure.

As part of a European Concerted Action on Male Reproduction Capability an exposure assessment survey was conducted among seasonal workers in the fruit growing sector in the Netherlands. Dermal exposure to the fungicides captan and tolylfluanid was measured using cotton gloves (12 persons) and skin pads on several body parts (12 persons). In addition, a set of exposure data was used from a study conducted recently among Dutch fruit growers. For harvesting activities, re-entry time appeared to be an important determinant of dermal exposure to captan and tolyfluanid. Explained variance of regression models was moderate to high (range 0.30-0.87). For captan, calculated half-life times from the most recent exposure survey were lower (glove data: 5 days; pad data: 6 days) compared with half-life times based on the previously conducted study (11 days). Possible explanations for the discrepancy are discussed. For tolylfluanid, estimated half-life times during harvesting were 2 and 3 days, based on pad and glove data, respectively. Prediction of captan exposure during other crop activities appeared to be far more difficult (explained variance equal to 0.06), although the estimated half-life time was comparable with that for harvesting. The data suggest that re-entry time gives useful information to group workers in broad exposure categories. Nonetheless, it was concluded that large studies are needed to evaluate the importance of re-entry time in more detail.

Individual-based and group-based occupational exposure assessment: some equations to evaluate different strategies.

Basically, two strategies can be considered for the analysis of hazardous pollutants in the work environment: group-based and individual-based strategies. This paper provides existing and recently derived equations for both strategies describing the influence of several factors on attenuation and on the standard error of an estimated linear regression coefficient relating a continuous exposure variable and a continuous health outcome via a simple linear regression model. We applied these equations using exposure variability information from industry-wide surveys over the past decade in order to gain more insight into the effects of various sources of exposure variability on choices among different analysis strategies. In general, for the modeling scenario considered here, there is not a straightforward criterion for choosing an optimal analysis strategy. Researchers have to decide between individual-based strategies generating precise, though biased, estimates or group-based strategies generating less precise but essentially unbiased estimates. For most exposure variability scenarios evaluated, an individual-based strategy yielded substantial attenuation. It is the authors' contention that the choice between individual-based and group-based strategies should be based on validity, rather than on precision, of the estimated exposure-response coefficient.

[Exposure to pseudo-estrogens and the quality of sperm]. / Blootstelling aan pseudo-oestrogenen en spermakwaliteit.

Some synthetic chemicals and natural compounds occurring in vegetables or animal food products mimic endogenous hormones, especially oestrogens, or may have a general action of disturbing hormonal status. It is assumed that intrauterine exposure to these compounds may have an adverse effect on development, differentiation and function of the genital organs of the male foetus. In a worldwide discussion a supposed drop in human sperm quality is related to foetal exposure to chemicals with oestrogen activity. Experimental animal evidence suggests that foetal exposure to compounds with oestrogenic activity may influence reproductive capabilities. In addition chemicals such as diethylstilbestrol (DES) in humans and dichlorodiphenyltrichloroethane (DDT) in wildlife influence the reproductive system. There is no conclusive evidence of decreasing semen quality in general.

Intraindividual variability and redundancy of semen parameters.

We analyzed two databases comprising repeated semen analyses of male patients visiting a fertility clinic in the Netherlands to assess intra- and interindividual variability for several semen parameters. We calculated reliability coefficients to estimate the attenuation of the slope if semen parameters are used to predict the probability of conception in regression models. Reliability was lowest for morphology (Population A: R = 0.48, Population B: R = 0.54), but somewhat better for motility (Population A: R = 0.66, Population B: R = 0.71) and count (Population A: R = 0.79, Population B: R = 0.81). Semen concentration had the largest reliability coefficients (Population A: R = 0.84, Population B: R = 0.84). Stimulations using empirical variance components indicated that using semen parameters as endpoints in case-referent studies might substantially underestimate measures of association. The results showed that most semen parameters were just moderately redundant (range: Kappa = 0.28 to Kappa = 0.45); only agreement between concentration and count was substantial (Population A: Kappa = 0.84, Population B: Kappa = 0.80). Hence, epidemiologic studies focusing on male infertility should take into account a variety of parameters.

Changes in ventilatory function in grain processing and animal feed workers in relation to exposure to organic dust.

OBJECTIVES: The effects of organic dust exposure on the configuration of the maximum expiratory flow volume (MEFV) curve was examined multivariately. METHODS: Data from 390 male workers in the animal feed industry in The Netherlands were analyzed. A multivariate technique called nonlinear canonical correlation analyses was used to study the relationship between a set of organic dust exposure variables and a set of ventilatory function variables. RESULTS: The results indicate an almost independent effect of the overall mean organic dust exposure and the number of years of organic dust exposure on ventilatory function. Increasing mean organic dust exposure was associated with a decrease in both forced expiratory volume in 1 s (FEV1.0) and forced vital capacity (FVC) and decreased flows at high lung volumes only. Increasing number of years of dust exposure was associated with a decrease in FEV1.0 and a decrease in flow at all lung volumes, while the FVC seemed relatively constant. These two distinct patterns of reduction in ventilatory function may represent two different pathological processes. Whereas workers with prolonged exposure showed reduced values for all of the MEFV curve variables, except the FVC, those with only a few years of exposure especially showed a decrease in FVC and peak expiratory flow. The effect of current organic dust exposure was more evident for nonsmokers than for ex-smokers and current smokers. CONCLUSION: The major finding of this study was an independent effect of overall mean organic dust exposure and the number of years of organic dust exposure on the MEFV curve.