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2
2
지난 시간에 우리는
어떤 물질도 독성을 나타낼 수 있다. (물, 산소,
술, 커피, 에스트로겐, 인슐린, 탈리도마이드)
노출되는 경로에 따라 독성이 달라질 수 있다.
신약을 개발할 때 안전성을 검사하는 것이 매
우 중요하다.
모든 위험을 다 대비하기는 어렵다.
동물실험결과를 사람에게 직접적용하기 어렵
다.
Extrapolation의 개념을 알고 있다.
Side effects
therapeutic dose, non-targeted effects,
sometimes beneficial
minoxidil, prosca (hair-regrowth)
viagra
Toxic effects
overdose, any effects, harmful
FOR
acetaminophen (hepatotoxicity) REFERENCE
ONLY
1. Principles of toxicology
-Poison (toxic substance, toxic chemical, and
toxicant): Any substance injurious to humans
may be classified as a poison (NaCl, ethanol,
oxygen etc.)
-“The dose makes the poison”
-LD50: the dose of a chemical that kills 50%
먼저, 소주 몇 병이 (반수)치사량이라고
생각되나요?
LD50 of Ethyl Alcohol
LD50
Rat
NaCl 4 g/kg
MSG 16 g/kg
Human
NaCl 280 g/70 kg
MSG 1,120 g/70 kg
MSG (Monosodium glutamate)
PO similar to IV
easy and rapid absorption
Advantage of LD50 test
1. First approximation of hazards to human
2. Information concerning mode of action
3. Rapidly completed
4. Information for experimental design
1. 어떻게 측정할까요?
2. 보통 몇 마리의 동물을 사용할까요?
3. 앞에서 말한 것 이외의 문제점은?
미국 FDA는 보톡스 판매를 위해 복강 주사 후
LD50 실험을 요구 한다.
보통 100 마리정도 사용한다.
근육마비, 시력손상, 횡경막 마비, 질식 사, 실험
이 끝나 안락사 되기까지의 고통으로 미루어 잔
인한 실험이다.
잠깐 쉽시다!
Lethal dose (LD50): ED50 TD50
Therapeutic index (TI): LD50/ED50
Margin of Safety (MOS): LD1/ED99
Percent activity
Toxicity testing
General toxicity test
Acute toxicity test
Subacute toxicity test
Chronic toxicity test
FOR
REFERENCE
ONLY
Acute toxicity test
- a single exposure
- up to 14 days
- measure LD50, TI, MOS
- 3 or more species (including nonrodent)
Subacute toxicity test
- 1 or more exposure / day
- 3 doses (therapeutic dose to toxic dose)
- 4 to 13 weeks
- 2 or more species(mouse, dog)
- blood, liver, kidney function test
- sacrifice, autopsy, histological exam
Dose-response experiment의 목적은?
so that the best and safest dose can be
found and to discover the point at which a
compound is too poisonous to administer.
Toxicity
Dose
Chronic toxicity test
- 1 or more exposure / day
- 3 doses (therapeutic dose to toxic dose)
- 6 to 24 months
- 2 or more species
- blood test, function test during expose
- fertility, carcinogenicity, teratogenicity…
독성시험의 주요 원칙 1
독성시험결과를 인체에 응용할 수 있는 적절
한 방법이어야 한다.
물티슈 피부자극시험, 경구투여독성시험
가습기 세정제 흡입독성시험
동물 마다 독성이 다를 수 있다
TCDD Hamster 5 mg/kg
female Guinea pig 0.0006 mg/kg
독성시험의 주요 원칙 2
고용량 실험으로 저용량의 위험성을 평가한
다.
발암독성이 0.01% 발생한다고 가정할 때
인구 5천만명 당 5천명이 발생
실험동물 1만 마리당 1마리 발생
ADI = NOAEL/100
scaled by safety factor (100)
animal to human differences (10)
differences between humans (10)
Generally acceptable risk of chemicals
from 1/105 to 1/106 lethality
Accident mortality
이 물질을 섭취하
Automobile 1 in 5,000
면 ( )명당 한 명이 Drowning 1 in 30,000
죽는답니다. Air travel 1 in 100,000
Lightning 1 in 2,000,000
Nuclear 1 in 5,000,000
Human
The 3Rs principle
Reduction: reduce the number of
animals used in experiments, LD50
Refinement: reduce animals suffering,
animal care facility
Replacement: replacing experiments on
animals with alternative techniques
including cell culture, simulation
Extrapolation의 개념을 잘 이해하지 못하
면…
Earvin "Magic" Johnson, Jr. (born August 14, 1959) is a retired American
professional basketball player who played point guard for the Los Angeles
Lakers of the NBA. He won a championship and an NBA Finals Most
Valuable Player Award in his rookie season, and won four more
championships with the Lakers during the 1980s. Johnson retired abruptly
in 1991 after announcing that he had contracted HIV, but returned to
play in the 1992 All-Star Game, winning the All-Star MVP Award. After
protests from his fellow players, he retired again for four years, but
returned in 1996, at age 36, to play 32 games for the Lakers before
retiring for the third and final time.
Johnson's career achievements include three NBA MVP Awards, nine NBA
Finals appearances, twelve All-Star games, and ten All-NBA First and
Second Team nominations. He led the league in regular-season assists
four times, and is the NBA's all-time leader in average assists per game,
at 11.2.[3] Johnson was a member of the "Dream Team", the U.S.
basketball team that won the Olympic gold medal in 1992. After leaving
the NBA in 1992, Johnson formed the Magic Johnson All-Stars, a
barnstorming team that travelled around the world playing exhibition
games.[4]
Extrapolation의 개념을 잘 이해하지 못하
면…
Johnson was honored as one of the 50 Greatest Players in NBA History in
1996, and enshrined in the Basketball Hall of Fame in 2002.[5] He was
rated the greatest NBA point guard of all time by ESPN in 2007.[6] Since
his retirement, Johnson has been an advocate for HIV/AIDS prevention
and safe sex,[5] as well as an entrepreneur,[7] philanthropist,[8] broadcaster
and motivational speaker.[9] Named by Ebony Magazine as one of
America's most influential black businessmen in 2009,[10] Johnson has
numerous business interests, and was a part-owner of the Lakers for
several years. Johnson also is part of a group of investors that purchased
the Los Angeles Dodgers in 2012.
Extrapolation의 개념을 잘 이해하지 못하
면…
1990년대 초반 Magic Johnson HIV감염,
Freddie Mercury 사망 등이 알려지면서
수십억 달러의 연구비를 동물실험에 사용
2
2
정리하면
LD50의 의미와 구하는 방법을 알고 있다.
LD50의 장점과 한계를 알고 있다.
일반독성시험과 특수독성시험을 구분할 수 있다.
급성독성시험, 아급성독성시험, 만성독성시험을 구분할 수 있
다.
치료지수 TI의 의미를 알고 있다.
독성시험에 있어 Dose-response 실험이 중요함을 알고 있다.
독성시험은 인체에 적용할 수 있는 적절한 시험법을 사용해
야 한다.
고용량실험으로 저용량의 위험성을 평가한다.
어떤 물질의 안전성을 입증하는 것보다 독성을 특정 짓는 것
이 중요하다.
NOAEL의 개념을 알고 있다.
ADI의 개념을 알고 있다.
밥 먹고 다닙시다!