Refinement of decision tree to assess the consequences of increased serum ALP in dogs: Additional analysis on toxicity studies of pesticides evaluated recently in Japan.

Recently we provided a new interpretation that increased serum ALP in dogs is not adverse if no hepatotoxic finding coexists in the analysis of toxicity studies of over 200 pesticides evaluated in Japan (Yokoyama et al., 2019). We also proposed a decision tree to evaluate the adversity of the increased ALP. The present analysis was conducted to validate the reliability of this interpretation with 129 pesticides more recently evaluated. Before applying, the decision tree was revised to be consistent in all steps. The pesticides showed similar characterization of increased ALP to the previous analysis in that the increase was more frequent than in rats and that liver hypertrophy and hepatotoxicity commonly coexisted with an increase in ALP in dogs. When short- and long-term studies of 58 pesticides inducing ALP activity in dogs were applied to the revised tree, the increased ALP in 8 pesticides was judged not adverse in either study. The revision of the tree did not affect the NOAEL judgment of these pesticides; however, the revised routes contributed to the judgment more robustly. This study showed the reliability of our interpretation and applicability of the decision tree to evaluate the adversity of increased ALP in dogs.

Scientific and Regulatory Policy Committee Points to Consider Review: Inclusion of Reproductive and Pathology End Points for Assessment of Reproductive and Developmental Toxicity in Pharmaceutical Drug Development.

Standard components of nonclinical toxicity testing for novel pharmaceuticals include clinical and anatomic pathology, as well as separate evaluation of effects on reproduction and development to inform clinical development and labeling. General study designs in regulatory guidances do not specifically mandate use of pathology or reproductive end points across all study types; thus, inclusion and use of these end points are variable. The Scientific and Regulatory Policy Committee of the Society of Toxicologic Pathology (STP) formed a Working Group to assess the current guidelines and practices on the use of reproductive, anatomic pathology, and clinical pathology end points in general, reproductive, and developmental toxicology studies. The Working Group constructed a survey sent to pathologists and reproductive toxicologists, and responses from participating organizations were collected through the STP for evaluation by the Working Group. The regulatory context, relevant survey results, and collective experience of the Working Group are discussed and provide the basis of each assessment by study type. Overall, the current practice of including specific end points on a case-by-case basis is considered appropriate. Points to consider are summarized for inclusion of reproductive end points in general toxicity studies and for the informed use of pathology end points in reproductive and developmental toxicity studies.

[Classification of Histopathological Findings in the Liver Cited in the Pesticides Risk Assessment Reports Published by the Food Safety Commission of Japan and Thesaurus Construction Based on the International Harmonization of Nomenclature and Diagnostic (INHAND) Criteria].

Histopathological findings are important to the understanding of toxicity profiles of pesticides. The liver is often a target organ of chemicals. In the present study, histopathological findings in the liver cited in the pesticides risk assessment reports published by the Food Safety Commission of Japan were classified. The histopathological findings were obtained in repeated-dose 90-day oral toxicity studies of mice, rats and dogs and carcinogenicity studies of rodents. After the classification, a thesaurus was constructed based on the International Harmonization of Nomenclature and Diagnostic (INHAND) Criteria. We recommend the use of INHAND criteria in risk assessment reports to improve mutual understanding between applicants and risk assessors.

[Basic principles of interpretation of hepatocellular hypertrophy in risk assessment in Japan].

This article provided a scientific basis for determining whether liver hypertrophy, a common change in the liver induced by xenobiotics in toxicological studies, is an adaptive or adverse event. To maintain homeostasis in the whole organism, the liver frequently responds to xenobiotic exposure by increasing metabolic capacity via nuclear receptor activation. The resuiting hepatic adaptive responses (hepatocellular hypertrophy and increased relative liver weight) are potentially beneficial to the organism in providing increased capacity to respond to chemical-induced stress. However, excessive responses should be recognized as adverse. Practically, hepatocellular hypertrophy leading to the following alterations should be considered adverse: 1) hepatocellular degeneration/ necrosis, whether or not accompanied with inflammatory reaction, 2) changes indicating damage to biliary tracts, 3) disruption of fat metabolism, 4) pigmentation, 5) deviation from typical localization or morphological features of hypertrophied hepatocytes.

Interventional study for improvement of lung cancer screening rate.

The aim of this study is to evaluate whether leaflet distribution affects lung screening rate, and what factor affects the motivation of consultation. Men and women aged 40 to 59 were targeted to improve screening rate of ages for cancer screening, especially in their prime. Each 1,000 subject, a total of 2,000 were selected and divided into 8 groups in consideration of age group by random sampling method. This group was further divided into two groups, an intervention group including subjects distributed a leaflet and a non-intervention (control) group. A survey was conducted by postal self-administered survey forms. Collection rate was 21.6% for the intervention and 17.6% for the control group. The numbers of respondents who answered that this leaflet was effective for motivation of consulting lung cancer screening and the leaflet was ineffective, were 120 (60.0%) and 80 (40.0%), respectively. This indicated that the leaflet was clearly effective (p<0.01). Actual cancer screening rate was 38.8% for the intervention group and 37.7% for the control group. It was shown that distribution by mail of even a single leaflet made by National Cancer Center was effective for motivation of consultation of lung cancer screening.