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알레르기 유발 향료의 흡입 감작성 평가·예측기법 연구

Other Titles
 A study on the methods for evaluating and estimating inhalation sensitization of allergenic fragrances 
Authors
 김승은 
College
 Graduate School of Public Health (보건대학원) 
Degree
석사
Issue Date
2019
Abstract
향료(Fragrance)의 주요 노출 경로는 흡입이며 일부 접촉 알레르겐의 흡입 노출 시 개인에 따라 염증 및 호흡기 질환을 일으킬 수 있다고 알려져 있다. 하지만 현재 흡입 민감성 연구는 부족한 실정으로 향료의 경피 감작성 독성값(NESIL; No expected sensitization induction level)은 LLNA시험 등의 자료를 기반으로 제시되어있지만, 흡입 감작성 독성값에 대한 연구는 부족하여 향료의 흡입 정량적 위해평가는 제한적이다. 따라서 본 연구에서는 알레르기 유발 향료 26종의 경피 감작성 독성값을 기반으로 흡입 감작성 독성참고치를 추정하고, 방향제 및 향수 중 향료의 함유수준을 분석하고 흡입 노출량를 평가하여, TTC 접근법을 기반으로 흡입 감작성 독성참고치와 노출량을 비교하여 향료의 흡입 감작성을 평가하였다. 경피 감작성 독성값에서 흡입 감작성 독성참고치를 추정하기 위해 경로외삽기법을 적용하였다. 먼저 경로외삽을 위해 향료는 경피 및 흡입 노출 시 제4형과민반응을 일으킴을 확인하였으며,‘향료는 노출경로에 관계없이 동일한 알레르기 반응 기전을 일으킨다’라는 이론적 근거를 정립하였다. 외삽을 위한 시작 독성값은 경피 LLNA에서 산출된 EC3(%)으로 결정하였으며, 흡입 감작성 독성참고치 추정 모식도를 도출하였다. 향료의 흡입 감작성 독성참고치 추정을 위한 산출수식을 도출하고 외삽 보정계수인 불확실성 상수를 결정하였다. 외삽은 총 3단계로 구분하였으며, 첫 번째 단계로 경피 EC3(%)에서 경피 ED3(㎍)으로 변환하는 산출수식은 일일적용량, 총 노출기간, 피부 흡수율을 적용하여 도출하였다. 두 번째 단계로 경피 ED3(㎍)에서 흡입 EC3(㎍/㎥)으로 외삽하는 산출수식은 흡입민감성보정상수, 시험동물의 호흡률 및 흡입흡수율을 적용하여 도출하였다. 마지막 단계로 흡입 EC3(㎍/㎥)에서 흡입 감작성 독성참고치(㎎/㎥)를 추정하는 산출수식은 종간불확실성상수 및 종내민감성불확실성상수를 적용하여 도출하였다. 흡입민감성보정상수는 피부 및 흡입 알레르겐 물질의 경피 EC3값과 흡입ED3값 사이의 상관관계 사이의 기울기값을 적용하여 10으로 결정하였다. 방향제 및 향수 중 향료 18종의 함량 시험 결과, 차량용 방향제 거치식 제품군에서 물질의 누적 함량이 가장 높았고, 물질 중 Linalool이 가장 높게 검출되었다. 흡입 노출량 평가 결과, 차량용 방향제 디퓨저에서 물질의 누적 흡입 노출량이 가장 높았으며, 분사형 제품에 비해 지속적 방출 노출 시나리오가 적용되는 디퓨저 및 거치식 제품이 상대적으로 높게 추정되었다. 추정된 향료 26종의 흡입 감작성 독성참고치는 TTC접근법에 기반하여 물질별 독성참고치 값의 크기에 따라 ClassⅠ,Ⅱ,Ⅲ 등급으로 구분하고, 각 등급별 p-RfC(proposed-Reference Concentration)으로 ClassⅠ 0.1 ㎎/㎥, ClassⅡ 0.01 ㎎/㎥, ClassⅢ 0.001 ㎎/㎥ 값을 적용하였다. p-RfC와 제품군 및 물질별 흡입 노출량을 비교한 결과, 대부분의 물질 노출량은 p-RfC 보다 낮았으며 차량용 방향제 중 일부 검출 함량이 높은 Linalool 및 Benzyl salicylate 의 노출량만이 p-RfC를 초과하였다. 이상의 연구 결과를 통해 Linalool 및 Benzyl salicylate는 보수적으로 예측한 흡입 독성값이 노출량을 초과하였기에 향후 포괄적 위해평가 또는 추가 독성시험 연구가 필요한 우선순위 물질로 판단된다. 향후 연구에서는 흡입 LLNA와 같은 용량-반응 평가에 기반한 독성시험연구가 수행되어지고, 신뢰도 높은 독성시험자료를 기반으로 알레르기 유발 향료의 흡입 감작성평가 연구가 수행되어져야 할 것이다. The main route of exposure to fragrance is inhalation, and it is known that some contact allergens may cause inflammation and respiratory diseases depending on the individual upon inhalation exposure. However, there are only few studies on inhalation sensitivity. Although dermal No-Expected-Sensitization-Induction Level (NESIL) has been proposed, studies on inhalation NESIL have been lacking, and quantitative risk assessment of inhalation of fragrance is limited. Therefore, in this study, the inhalation sensitization toxicity reference value was estimated based on the transdermal NESIL of 26 allergenic fragrances, the content level of fragrance was analyzed in some products, and the inhalation exposure dose was evaluated. Moreover, the inhalation sensitization toxicity was assessed by comparing the inhale exposure to inhalation toxicity reference value using the TTC approach. The route-to-route extrapolation technique was applied to estimate the inhalation sensitization toxicity reference value at the transdermal NESIL. First, for the route-to-route extrapolation, a theoretical basis, ‘Fragrance induces the same allergic reaction regardless of the exposure path’, was established. The starting toxicity value for extrapolation was determined to be EC3 (%) calculated from transdermal LLNA, and the inhalation sensitization toxicity reference value estimation model using the uncertainty factor was derived. The calculation formula for estimation of the inhalation sensitization toxicity reference value of fragrance was derived, and the uncertainty constant, which is an extrapolation correction factor, was determined. The extrapolation was divided into three steps. At the first step, the formula for conversion from transdermal EC3 (%) to transdermal ED3 (㎍) was derived. For the formula, the daily dose, total exposure period, and skin absorption rate were applied. In the second step, the formula for extrapolating from transdermal ED3 (㎍) to inhalation EC3 (㎍/㎥) was derived. For the formula, inhalation sensitivity correction factor, respiration rate and inhalation absorption rate of the test animal were applied. In the final step, the formula for estimating inhalation sensitization toxicity reference value (㎎/㎥) at inhalation EC3 (㎍/㎥) was derived by applying interspecies uncertainty factor and intraspecies sensitivity uncertainty factor. The inhalation sensitivity correction factor was determined to be 10 by applying a slope value of the correlation between the dermal EC3 and inhalation ED3 of the skin and the inhaled allergen. As a result of assay of 18 kinds of fragrance among air fresheners and perfumes, the accumulation amount of substances was the highest in the fixed car air freshener, and the detection amount of linalool was the highest among the substances. As a result of assessment on the inhalation exposure dose, the accumulated inhalation exposure dose of substances was the highest in the car diffuser. Compared to the spray product, the exposure doses of the diffuser and fixed product, to which the sustained release exposure scenario is applied, were estimated to be relatively higher. Based on the TTC approach, the estimated inhalation sensitization toxicity reference values of 26 kinds of fragrance were classified into Class I, II, and III according to the size of the RfC value for each substance based on the same class approach. As p-RfC (proposed Reference Concentration), 0.1 ㎎ /㎥, 0.01 ㎎/㎥, and 0.001 ㎎/㎥ were applied to Class I, II, and III, respectively. As a result of comparing the p-RfC and the inhalation exposure dose for each product group and substance, the exposure doses of most substances were lower than p-RfC. In the car air freshener, only the exposure doses of some substances such as linalool and benzyl salicylate, whose detection amount is high, exceeded p-RfC. As the conservative estimate for inhalation toxicity of Linalool and Benzyl salicylate exceeded the exposure rate according to the result of this study, a comprehensive risk assessment and further toxicity assessment are deemed necessary for these materials. A toxicity assessment based on dose-response evaluation such as inhalation LLNA and inhalation sensitization assessment study of allergenic fragrances based on the toxicity assessment data need to be performed.
Appears in Collections:
4. Graduate School of Public Health (보건대학원) > Others (기타) > 5. Others
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/178410
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