Health Hazard Assessment (HHA) Team, newly established in CRM, is led by Dr. Hajime Kawasaki with five scientists (a Senior Research Scientist, a post-doctor fellow and two technical assistants). Four major research topics of HHA team are followings:

1. Hazard assessment of industrial chemistry

CRM has already released detailed risk assessment documents for nine chemicals while others are under scrutiny. One of the major research targets of HHA team is to make scientifically sound toxicological review of the chemicals through accurate understandings of their toxicological profile as well as their toxicity mechanisms.

The reason why we are now reviewing the hazard assessments of existing chemicals ourselves is that even current available assessment report can easily become inadequate due to rapid growing knowledge of science, especially of life sciences, which is the ground of the hazard assessment of chemicals. 

Recently, by reviewing the existing assessment reports and related literature on 1,4-dioxane, we found different opinions among authorities on the mechanisms of carcinogenicity as well as the quantitative approach for extrapolation of the animal data to human safe dose (Table 1) regardless of employing the same animal data. We have examined the published recent analysis of the animal carcinogenicity data using physiological based pharmacokinetics (PBPK) model and reached to a new opinion, which has been published in “Risk assessment reports. Series 2. 1,4-Dioxane” (eds. Makino R. et al., Maruzen Publishers, 2005). 

Table 1 Different opinions on the carcinogenicity of 1,4-dioxane

	WHO	EU	NIC NAS	IRIS (USA)	BUA (Germany)	MHLW ( Japan)	ME ( Japan)	CRM
Target organ	Liver	Liver	Liver	Nasal cavity	Others	Liver	Not assessed	Liver
Threshold	Yes/No	Yes	Yes	No	Yes	No	−	Yes

WHO: World Health Organization, EU: European Union, NICNAS: National Industrial Chemicals Notification and Assessment Scheme (Australia), IRIS: Integrated Risk information System (USA), BUA: Bundesanstalt fur Arbeitsschutz und Arbeitsmedizin, MHW: Ministry of Health, Labor and Welfare (Japan), ME: Ministry of Environment (Japan)

2. Reviewing the existing PBPK models and application of them to the risk assessment of chemicals

PBPK modeling is an important tool for improving the accuracy of human risk assessment for hazardous substances. Proper use of this technique can reduce uncertainties that currently exist in risk assessment procedures by providing more scientifically credible extrapolations across species and route of exposure, and from high experimental dose to potential environmental exposures. In addition, the outcome of PBPK models enables us to predict the toxicity mechanisms of chemicals to a certain extent. However, employing the outcome of PBPK models without due consideration should be admonished. Thus, efforts will be made to develop procedures to validate PBPK models for the purpose of using the outcome in our assessments.

 
3. Hazard assessment of industrial nano-materials

Nanomaterials, one of the dimensions of which is between 100 and 10 nm, are being used to improve existing products and at least 15% of all commodity products are estimated to contain nanomaterials within a decade due to their unexpectedly unique and novel properties. And thus, nano-specific human health hazard has become one of the emerging issues to be solved. We are now studying the nano-specific biological responses using cultured cells to develop in vitro toxicity testing methods. 

 
4. Risk-assessment of formaldehyde

Formaldehyde induces nasal tumors in several bioassays using rats after prolonged inhalation exposure. In contrast to animal bioassays no consistent positive results in terms of nasal tumor induction were obtained in several cohort studies on occupationally exposed populations like pathology scientists, human anatomy practioners or factory workers who were regularly exposed to high concentration of formaldehyde. Although formaldehyde are positive in most of the in vitro mutagenicity tests, the mechanisms for the nasal tumor induction are considered to be associated with sustained non-specific cellular proliferation induced by its strong irritability to the topical mucosal area because formaldehyde are negative in many in in vivo genotoxicity tests. The postulated mechanism of tumor induction by formaldehyde indicates that the quantitative risk assessment of formaldehyde to human health can be estimated from NOAEL (non-observable adverse effect level) with a suitable uncertainty factor. With regard to the health hazards by formaldehyde by inhalation route, the lowest concentration that induces irritation to nose and throat in humans after short-term exposure is 0.1 mg/m³ and this is over one order of magnitude lower than a presumed threshold for cytotoxic damage to the nasal mucosa which is associated with nasal tumor induction. Therefore, WHO-ROE (World Health Organization- Regional Office for Europe) recommended an air quality guideline level of 0.1 mg/m³ as a 30-minutes average for formaldehyde. The postulated tumor induction mechanisms of formaldehyde indicate that the assessment of exposure concentration level in the air is more important than that of total inhaled quantity of chemical when a quantitative risk assessment of formaldehyde in the air to human health is conducted.