The authors reviewed the English language papers concerning chronic health effects of agricultural chemicals, focusing on the incidence of cancer in pesticide users. These papers were collected using MEDLINE between 1988 and 1998 as a referencetool. According to the standard study design, the epidemiological literature is classified into cohort studies and case-control studies. These studies suggested the association between pesticides and various types of cancer such as soft tissue sarcoma, non-Hodgkin's lymphoma, lung cancer, and breast cancer. Categories of pesticides included in these studies, varied greatly, including herbicides and insecticides.
In this paper, we discussed about such problems as the selection of control groups and the assessment of pesticide exposure levels, which may pose some problems in conducting epidemiological research on the relationship between pesticides and cancer.
A model for a method of epidemiological study of health hazards due to pesticide exposure was also presented.

Objective: Pharmaceutical manufacturers conduct drug use-results surveys (DUSs) for drug reexamination applications in Japan. However, most DUSs are single-cohort studies to confirm drug safety; therefore little information is obtained from a DUS for safety comparison with other drugs. Integrating DUS data is a novel method to compare drug safety profiles among drugs. This study examined the usefulness of integrating DUS data.
Design: Active surveillance
Methods: We integrated DUS data obtained from two DUSs of antihypertensive drugs-a calcium channel blocker (CCB), azelnidipine (CalblockR), and an angiotensin-receptor blocker (ARB), olmesartan medoxomil (OlmetecR)-with similar study protocols. Both studies were conducted by the same pharmaceuticalcompany. Matching patients using propensity scores, we examined whether the DUS results could be applied to pharmacoepidemiology data resources for hypothesis strengthening. Safety outcomes included vasodilation-related events, which are typical adverse drug reactions (ADRs) to CCB. The incidence of safety outcomes was compared by conditional logistic regression models. Two definitions for safetuoutcomes were employed: definition 1, physician-reported adverse events; and definition 2, physicianreported ADRs.
Results: In a total of 7196 patients included in the analysis, the propensity-matched patients were well balanced. Most safety outcomes were detected in the CCB group including a significant increase in vasodilation-related events (odds ratio for definition 1 versus ARB group, 1.75; 95% confidence interval,1.01-3.03).
Conclusion: Integrated DUS data collated by pharmaceutical manufacturers following clear criteria are potentially useful to commence pharmacoepidemiology studies designed to strengthen hypotheses.

An epidemiological survey on allergic conditions of 58 male (aged 38.6±11.8yrs) and 47 female (aged 42.2 ± 9.6yrs) farmers engaged in growing chrysanthemums.
Among the subjects, 47% of males and 62% of females had complaints of at least one of inquired allergic symptoms associated with the work. The immediate type of allergic reaction on nasal and/ or upper respiratory system raised in the process of sorting flowers in the working room and delayed ype of contact dermatitis in pinching the lateral bud of chrysanthemums or spraying agricultural chemicals in the field were the main complaints of those farmers.
Incidence of positive reaction for patch testing to six kinds of chrysanthemums was 5% for males and 17% for females and that of eight kinds at agricultural chemicals was 34% and 45% for each sex. And relatively high incidence was also observed in those subjects from other immunological tests such as determination of serum immunoglobulin, prick testing and calculation of eosinophil in blood and rhinorrhoea.
There were 39 (67%) males and 36 (77%) females who had at least one of the abnormal finding of those test items above mentioned. However, not the particular kind of Chrysanthemum cultivated in that area was found to be strong causative allergen for the observed allergic conditions.
From these results, it is indicated that relatively high incidence of allergic disorders may be found in the chrysanthemum growers due to inhalation and/or contact of some kinds of allergens introduced from the process of growing to forwarding, such allergen as Chrysanthemum itself, agricultural chemicals and other elements.

Objective: The aim of this study was to establish the proper definitions of venous thromboembolism (VTE) and bleeding events for a healthcare database in Japan.
Study Design: Validation study.
Methods: The study comprised patients with VTE or who had undergone orthopedic surgery of the lower extremities and whose outpatient or inpatient medical information from April 1, 2008 to September 30, 2013 was available.  The source population of the database was derived from 100 acute-care hospitals.  The endpoints were VTE events (deep venous thrombosis [DVT], pulmonary thromboembolism [PE]) and bleeding events (bleeding requiring blood transfusion, intracranial hemorrhage, intraocular hemorrhage, upper gastrointestinal [GI] bleeding, and lower GI bleeding).  The frequent events with laboratory data were randomly extracted and evaluated, while all the infrequent events with laboratory data were extracted and evaluated.  Positive predictive value (PPV) was defined as the proportion of events judged to be clinical by medical experts of all the extracted events.  First, we conducted a test with a small number of cases and then revised the definitions of events.  Second, we extracted and evaluated data in 50 patients for VTE and bleeding events patients, based on which we defined the target PPV level between 60 and 70%.
Results: Of the 5,044,743 patients in the database, 36,947 patients underwent orthopedic surgeries of the lower extremities and 3,578 patients experienced a VTE event.  The PPV at the first evaluation was 80.0% (8/10) for DVT, 57.1% (4/7) for PE, and 27.3% (6/22) for bleeding events.  At the second evaluation using the revised definitions, the PPV were 75.0% (42/56) for VTE and 73.3% (33/45) for bleeding events.  Overall, the PPVs for VTE and bleeding events were over 70%.  The PPV of the VTE events were 76.9% (30/39) for DVT and 70.6% (12/17) for PE.  The PPVs of each type of bleeding event were over 70% except for intracranial hemorrhage (44.4%, 4/9).
Conclusion: The PPV was high for VTE events (75.0%) and bleeding events (73.3%).  The definitions used in this study are rational for the identification of VTE, DVT, PE, and bleeding events in the healthcare database in Japan.  The definition for each type of bleeding event should be investigated in further studies.

MHLW released a guideline for Risk Management Plan (RMP) in April 2012, in order to manage the risk of pharmaceutical products from the development stage towards post marketing period. The guideline suggests to determine Safety Specification and to develop Pharmacovigilance Plan (PVP) and Risk Minimization Plan aligned to the ICH E2E guideline. However, in some of the RMPs, which had been published online (as of August 2014), conventional (Special) Drug Use Results Surveys are planned as a “universal” PVP regardless of the impact, severity and characteristics of the risks. Our JPMA taskforce (Data Science Expert Committee) summarized report and published in August 2014. In this report, we explained how to evaluate safety events based on evidence level for safety specification and how to develop PVP. Also, we would like to propose KAIZEN activities for RMP improvement as follows:
1. In order to clarify the research question, rationale and evidence for safety specification should be evaluated carefully.
2. It is essential to be considered in advance how to collect and analyze the safety data for detecting safety specification during clinical development.
3. Safety profiles should be discussed thoroughly on DSUR development among stakeholders in order to clarify safety specification at NDA. Research questions for each different risk and missing information should be established according to PECO, which will flow into appropriate PVP planning.
4. Continuous PDCA cycling is critical for RMP. The first survey or research will bring you next research question (s).
We expect all stakeholders, including clinical development specialists in industry, regulatory authorities, and academia, to have better understating of RMP principle and to manage and implement it more appropriately in a scientific manner.

PURPOSE: The purpose of this study was to elucidate the efficacy and safety of carbonate apatite (CO₃Ap) granules in 2-stage sinus floor augmentation through the radiographic and histomorphometric assessment of bone biopsy specimens.METHODS: Two-stage sinus floor augmentation was performed on 13 patients with a total of 17 implants. Radiographic assessment using panoramic radiographs was performed immediately after augmentation and was also performed 2 additional times, at 7±2 months and 18±2 months post-augmentation, respectively. Bone biopsy specimens taken from planned implant placement sites underwent micro-computed tomography, after which histological sections were prepared.RESULTS: Postoperative healing of the sinus floor augmentation was uneventful in all cases. The mean preoperative residual bone height was 3.5±1.3 mm, and this was increased to 13.3±1.7 mm by augmentation with the CO₃Ap granules. The mean height of the augmented site had decreased to 10.7±1.9 mm by 7±2 months after augmentation; however, implants with lengths in the range of 6.5 to 11.5 mm could still be placed. The mean height of the augmented site had decreased to 9.6±1.4 mm by 18±2 months post-augmentation. No implant failure or complications were observed. Few inflammatory cells or foreign body giant cells were observed in the bone biopsy specimens. Although there were individual differences in the amount of new bone detected, new bone was observed to be in direct contact with the CO₃Ap granules in all cases, without an intermediate layer of fibrous tissue. The amounts of bone and residual CO₃Ap were 33.8%±15.1% and 15.3%±11.9%, respectively.CONCLUSIONS: In this first demonstration, low-crystalline CO₃Ap granules showed excellent biocompatibility, and bone biopsy showed them to be replaced with bone in humans. CO₃Ap granules are a useful and safe bone substitute for two-stage sinus floor augmentation.
Apatites ; Biopsy ; Bone Substitutes ; Carbon ; Dental Implants ; Giant Cells, Foreign-Body ; Humans ; Individuality ; Prospective Studies ; Sinus Floor Augmentation