To tolerate or to agree: A tutorial on tolerance intervals in method comparison studies with BivRegBLS R Package.

The well-known agreement interval by Bland and Altman is extensively applied in method comparison studies. Two clinical measurement methods are considered interchangeable if their differences are not clinically significant. The agreement interval is commonly applied to assess the spread of the differences. However, this interval is approximate (too narrow) and several authors propose calculating a confidence interval around each bound. This article demonstrates that this approach is misleading, awkward, and confusing. On the other hand, tolerance intervals are exact and can include a confidence level if needed. Tolerance intervals are also easier to calculate and to interpret. Real data sets are used to illustrate the tolerance intervals with the R package BivRegBLS under normal or log-normal assumptions. Furthermore, it is also explained how to assess the coverage probabilities of the tolerance intervals with simulations.

Inhalation and dermal exposure of workers during timber impregnation with creosote and subsequent processing of impregnated wood.

OBJECTIVES: Coal tar creosote oils are used as highly effective wood protectants for, e.g., railway sleepers, utility poles and marine pilings. For impregnation of wood, the hot creosote oil is mostly applied in vacuum processes and by hot-and-cold dipping. From the perspective of an occupational hygienist, creosote tar oils are problematic because they have a number of hazardous properties, including carcinogenicity. We have studied inhalation and dermal exposure in six and four impregnation plants, respectively, in Germany. Some plants were visited repeatedly, for up to five measurement campaigns conducted over several years. Inhalation and dermal exposure resulting from vacuum impregnation and from hot-and-cold dipping, as well as secondary exposure resulting from assembly of impregnated railway sleepers have been measured. Accompanying, human biomonitoring of the employees has been performed. METHODS: Inhalation exposure was measured using personal air samplers, collecting particles and vapours simultaneously. Dermal exposure was investigated by whole body dosimetry using disposable chemical protective coveralls and split leather gloves. 18 polycyclic aromatic hydrocarbons (PAHs) have been determined separately by high performance liquid chromatography (HPLC) or gas chromatography-mass spectrometry (GC-MS), respectively. For human biomonitoring 1-hydroxypyrene (1-OHP) in urine related to creatinine has been measured using HPLC. Both, pre- and post-shift values have been determined for this metabolite. RESULTS: Dermal exposure towards pyrene and the sum of the determined 18 PAHs as well as inhalation exposure to naphthalene, pyrene and the sum of the determined 18 PAHs are presented in this paper. The plants performing vacuum impregnation have employed different constructive, technical and organisational measures, and some measures have also changed between the different measurement campaigns. We have found that cooling the vacuum impregnation vessel before unloading can reduce inhalation exposure to about one-third. However, our data shows that installation of structural or technical risk management measures (RMM) did not always reduce the exposure as intended, and can even lead to increased exposure in adverse constellations. Dermal exposure was strongly affected by differences in the working procedures. Measurements performed during assembly of impregnated railway sleepers indicate that secondary exposure leads to lower inhalation, but similar dermal exposure compared to the impregnation processes. Also 1-OHP excretion rates are similar after impregnation process and after assembly of impregnated railway sleepers. CONCLUSION: Our recent data underlines that efficient reduction of the exposure resulting from impregnation with creosote requires sophisticated risk reduction strategies. Structural measures such as the enclosure of the loading area and technical measures like local exhaust ventilation shall be coordinated carefully with organisational measures and provision of personal protective equipment. The data presented here represents a broad bandwidth of current workplace situations in the creosote oil processing industry and is therefore suitable for risk assessment in related plants as well as under regulatory frameworks like the European Biocides Regulation. Each plant in this investigation was unique. Together they represent the whole width of this branch in Germany. Additionally, the number of plants and exposed workers is limited and relative low. Therefore, a comprehensive consideration and statistical analysis were not feasible.

Human biomonitoring of deoxynivalenol (DON) - Assessment of the exposure of young German adults from 1996 - 2021.

The mycotoxin deoxynivalenol (DON) is a frequently found contaminant in cereals and cereal-based products. As a German contribution to the European Joint Programme HBM4EU, we analysed the total DON concentration (tDON) in 24-h urine samples from the German Environmental Specimen Bank (ESB). In total, 360 samples collected in 1996, 2001, 2006, 2011, 2016, and 2021 from young adults in Muenster (Germany), were measured by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) after enzymatic deconjugation of the glucuronide metabolites. tDON was found in concentrations above the lower limit of quantification (0.3 µg/L) in 99% of the samples. Medians of the measured concentrations and the daily excretion were 4.3 µg/L and 7.9 µg/24 h, respectively. For only nine participants, urinary tDON concentrations exceeded the provisional Human biomonitoring guidance value (HBM GV) of 23 µg/L. Urinary tDON concentrations were significantly higher for male participants. However, 24-h excretion values normalized to the participant's body weight did not exhibit any significant difference between males and females and the magnitude remained unchanged over the sampling years with exception of the sampling year 2001. Daily intakes were estimated from excretion values. Exceedance of the tolerable daily intake (TDI) of 1 µg/kg bw per day was observed for less than 1% of all participants. TDI exceedances were only present in the sampling year 2001 and not in more recent sampling years while exceedance of the HBM guidance value was also observed in 2011 and 2021.

Occupational Exposure to Antibiotics in Poultry Feeding Farms.

Today, antibiotics are essential for effective treatment of infectious diseases both in human and veterinary medicine. The increasing development and distribution of antibiotic-resistant microorganisms are subject of concern. In some sectors of animal agriculture, such as poultry feeding farms, the application of antibiotics and hence occupational exposure is inevitable. In the past, numerous studies focussed on the occurrence of antibiotic-resistant bacteria in livestock farming, but little attention was paid to the employees. The exposure of workers to antibiotics was the focus of the study detailed in this article. Four biomonitoring campaigns monitoring systemic exposure of workers to antibiotics were run at two farms over four fattening periods. Urine samples of potentially affected employees were sampled and analysed for the antibiotics of interest by liquid chromatography-mass spectrometry. The highest antibiotic concentrations detected in urine samples exceeded the minimum inhibitory concentration of some bacteria strains. In some cases, the amount of antibiotics excreted over a time-period of 24 h indicated the exceedance of the tolerable daily intake.

Statistical considerations for calculation of immunogenicity screening assay cut points.

Most therapeutic proteins induce an unwanted immune response. Antibodies elicited by these therapeutic proteins may significantly alter drug safety and efficacy, highlighting the need for the strategic assessment of immunogenicity at various stages of clinical development. Immunogenicity testing is generally conducted by a multi-tiered approach whereby patient samples are initially screened for the presence of anti-drug antibodies in a screening assay. The screening assay cut point is statistically determined by evaluation of drug-naïve samples and is typically chosen to correspond to a false positive rate of 5%. While various statistical approaches for determination of this screening cut point have been commonly adopted and described in the immunogenicity literature, the performance of these approaches has not been fully evaluated. This paper reviews various statistical approaches for cut point calculation, evaluates the impact of sampling design and variability on the performance of each statistical approach, and highlights the difference between an 'average' or 'confidence-level' cut point in order to develop more specific recommendations regarding the statistical calculation of immunogenicity screening cut points.