1952V-series nerve agent

(1)

(2)

영화 ‘The Rock’1996

살상용으로 사용 - 가스 형태 의VX-

V-series nerve agent 합성1952 2017

김정남 암살 사건

살상용으로 사용 -액체 형태의 VX- 살충제로 사용

(3)

• O-ethyl-S-[2(diisopropylamino)ethyl]methylphosphonothiolate

• 무색 혹은 옅은 갈색

• 휘발성이 낮음

• 특별한 맛이나 냄새는 없음

• 신경제제 중 가장 독성이 강함

• Molecular weight = 267.4 g/mol

• Water solubility : 25℃ - 100g 당 30 g/L 15℃ - 100g 당 75 g/L

• 반감기는 pH와 온도, 환경에 따라 달라짐

- 25℃, pH 2~3 water : 15~40일 - 25℃, pH 7 water : 100일

- 대류권 : 0.24일 (≒ 6시간)

상대적으로 hydrophobic Sarin보다 100배 더 강한 독성

(4)

• 다른 신경제처럼 쉽게 물과 섞이지는 않지만, 물에 방출될 수는 있음

• VX에 오염된 물을 마시거나 피부 접촉되어 노출될 수 있음

• VX에 오염된 음식물을 섭취함으로써 노출될 수 있음

• 신체에서 천천히 분해되기 때문에 신체에 누적될 수 있음

Gas & Aerosol

Liquid

• 피부/안구 접촉, 흡입, 섭취 등을 통해 노출될 수 있음

• VX 기체에 접촉된 옷은 다시 VX를 방출할 수 있으므로, 전염 가능성이 있음

• VX 증기는 공기보다 무거워서 가라앉으므로 저지대 지역에서 노출 위험이 더 큼

(5)

Acetylcholine (ACh)

• 신경전달물질

• 일반적으로 운동신경이 자극되면 신경세포와

인접 근육세포 사이의 공간으로 방출됨

→ ACh이 근육세포에 흡수되면 근육 수축이 촉진됨

Acetylcholinesterase (AChE)

• 일정한 근육 수축 상태를 유지하기 위해 ACh을 비활성

물질인 아세트산과 콜린으로 가수분해함

Normal reaction

(6)

Acetylcholinesterase (AChE) Inhibitor

• AChE의 작용을 차단하여 ACh의 비활성화를 방해함

→ 신경세포와 근육세포 사이의 공간에 활성화 상태의 ACh를 축적시킴

→ 축적된 ACh에 의해 근육이 지속적으로 수축됨

In the presence of VX

(7)

중추신경계 공격해 두통과 통증 유발

근육조직의 경련, 심장발작, 호흡곤란 등 발생 자율신경계 파괴해 땀· 눈물 ·침 등 액체를 계속 방출하게 함

저용량, 단기간

노출 시 증상 감염 경로에

따른 치사량

흡입시 1㎥당 30-50mg (1분 기준)

피부 접촉시 10mg (1㎥ 기준)

고용량, 장기간 노출 시 증상

수초~18시간 내에 사망

(8)

 신속하게 오염된 옷벗기

 VX에 노출된 의류 등에 접촉 금지

 비누로 온몸을 흐르는 물에 씻기

 시력이 흐려지는 현상이 있 으면, 눈을 10~15분 정도 물 에 담구기

노출된 경우 피부에 공기 중에

노출된 경우 오염된 음식물을

섭취한 경우 모든 경우

즉시 약물 사용

해독제 : atropine, pralidoxime 진정제 : diazepam

 VX 노출 지역을 떠나서 신선 한 공기 마시기

 가능한 한 높은 지점으로 피 하기

 토사물 흡인, 식도 손상 등의 합병증을 유발할 수 있으므 로, 억지로 구토하지 않기

 희석시키기 위해서 음료 마 시지 않기 (효과 X)

(9)

두 여성 용의자가 맨손에 독극물(VX)을 바름

1 2

두 여성 용의자가 짧은 시차를 두고

김정남에게 접근해 그의 얼굴을 만짐

“두 여성 용의자가

서로 다른 물질을 손에 발라두고 번갈아 문질렀다는 추론 가능 !”

(10)

Binary form

• 상대적으로 무해한 두 가지 화합물을 결합하여 치명적인 독성을 가진 신경제제를 만들 수 있음

→ 노출되고 일정 시간이 지난 후 화학작용이 일어나 뒤늦게 강한 독성이 발현됨

“독살을 실행한 여성 용의자 중 한 명이 구토 등의

독극물 중독 증세를 보이고 있음”

Agent

QL Agent

NE

주성분 촉매제

VX2

독성 신경제제

“김정남이 피습 후 최소

30분간 의식을 유지한 점도 이런 가설을 뒷받침함”

(11)

http://www.bbc.com/news/world-europe-40896899

Fipronil and Bifenthrin

(12)

Fipronil

▶ A broad-spectrum phenylpyrazole insecticide.

1996 (U.S. Environmental Protection Agency) CAS registry number : 120068-37-3

▶ A white powder with a moldy odor

▶ Ants, beetles, cockroaches, fleas, ticks,

termites, mole crickets, thrips, rootworms, weevils, and other insects

Granular turf products, seed treatments, topical pet care products, gel baits, liquid termiticides, and in agriculture

(±)-5-amino-1-(2,6-dichloro-α,α,α-trifluoro-p-tolyl)- 4-trifluoromethylsulfinylpyrazole-3-carbonitrile 2-methylbiphenyl-3-ylmethyl (Z)-(1RS,3RS)-3-(2-chloro-3,3,3-trifluoroprop-l-enyl)- 2,2-dimethylcyclopropanecarboxylate

Bifenthrin

▶Insecticide, Pesticide

1985 (U.S. Environmental Protection Agency) Type I, non-cyano pyrethroid

with isomeric enrichment (1S, 3S and 1R, 3R) CAS registry number : 82657-4-3

▶Pale tan to off-white in color

Crystalline, waxy solid or viscous liquid Weak, aromatic odor

▶Cereals, cotton, corn, alfalfa, hay, grass seed,

some fruits, ornamentals, and vegetables.

Against a wide range of insects and mites

(13)

Mode of action

BASF, Insecticide mode of action-technical training manual

http://www.biomagazine.gr/index.php/site/article/38/25/BIO%20Environment/Mechanisms-of-insecticide-resistance

Fipronil

“GABA-gated chloride channel antagonist”

Bifenthrin

“Sodium channel modulators”

(14)

https://ipmworld.umn.edu /bloomquist-insecticides

(15)

(16)

http://www.pctonline.com/article/pct1011-insecticide- information/

(17)

(18)

(19)

(20)

Applied Ecology and Environmental Sciences, 2013, 1, 33-36

Bifenthrin

• Natural extract  Chemical modification

• Rapidly immobilize and paralyze targeted insects

• Effective by contact or ingestion

• Interfering with the sodium channel gating

 by delaying the closure of the sodium channel

• Channel open time : Type I < Type II

Toxicology 171 (2002) 3–59

(21)

▶ Non-target Organisms

• Same for mammals and invertebrates

• Pyrethroids are less toxic to mammals compared to insects

because of mammals' higher body temperature, larger body size, and lower sensitivity of the ion channel sites

• Pyrethroids other than bifenthrin  fish and gill-breathing aquatic insects by inhibiting ATP

Canadian Association of Physicians for the Environment, 2016, 1-13

Wakeling, Erin N., April P. Neal, and William D. Atchison.

"Pyrethroids and their effects on Ion Channels."

Pesticides-Advances in Chemical and Botanical Pesticides. InTech, 2012.

▶ Target Organisms

Delaying the closure the sodium channel (Opening of sodium channel)

 Inducing depolarization

 Rapid action on the cerebral ganglia of insect  Sudden shock, “Knock-down” effect

 Hyperexcitation (rapid, brief and inconsistent movement)

 Death

(22)

Fipronil (Phenylpyrazoles)

▶ Target and non-target organisms

• Contact or ingestion

• Blocking GABA-gated chloride channels  Inhibiting the opening of the chloride ion channels  Neuronal hyperactivity (inhibited depolarization)

• Lower binding affinity for mammalian receptors  less toxic

• Fipronil-sulfone(6 times), Fipronil-desulfinyl(9-10 times)

(23)

Trends in Parasitology, 2012, 28, 267-279

(24)

Main exposure path

Through the skin during application or

contact with treated surfaces

Vapor, fine droplets or

suspended dust particles in the air

• Toxicity of the pesticide to the skin

• Duration of the exposure

• Pesticide formulation

• Body part contaminated

Contaminated food or water

• General human population

• Small intestine

Blood stream

Entire body

(25)

Medical tests and monitoring

Bifenthrin

• HPLC-UV to detect and quantify bifenthrin and its primary metabolite 2-methyl-3-phenylbenzoic acid (MPA) in urine

• The method for evaluating exposure to bifenthrin and its metabolite has not been well-studied in humans, and its clinical significance is unknown.

Fipronil

• Blood sample or in the gastric lavage fluid  ELISA or liquid chromatography mass spectrometry

Environ. Sci. Technol., 2015, 49, 10038-10047

(26)

Bifenthrin – Acute toxicity

LD₅₀

Oral 43 mg/kg (mice)

53.4 mg/kg to 210.4 mg/kg (rat)

Dermal 2000 mg/kg after 24 hr exposure Non-irritating Inhalation 1.10 mg/L

http://npic.orst.edu/factsheets/archive/biftech.html#reprod

Toxicities

(27)

Sign of Toxicity - Humans

 Paresthesia (most common reported symptom from dermal exposure in occupational studies)

 Skin sensations : tingling, itching, burning, and numbness of the skin after dermal exposure

Temporary and reversible in a period of hours, sometimes lasting up to 48 hours Only at the site of dermal exposure and is not associated with systemic intoxication

 Inhalation  Respiratory and nasal irritation

 Ingestion  Sore throat, nausea, abdominal pain and vomiting almost immediately after ingestion. Increased oral secretions, ulcerations in the mouth, difficulty

swallowing, headache, dizziness and fatigue

 Symptoms less frequently reported include blurred vision, heart palpitations and tightness in the chest

(28)

Applied Ecology and Environmental Sciences, 2013, 1, 33-36

비염, 재채기, 인후찰상,

구내점막부종 및 후두 점막부종

(29)

LD₅₀ LOAEL NOAEL Oral 97 mg/kg (rat)

95 mg/kg (mice)

7.5 mg/kg 2.5 mg/kg fipronil-desulfinyl 15 mg/kg

Dermal >2000 mg/kg (rat) 354 mg/kg (rabbit)

- 5.0 Skin irritation

Mild eye irritation Inhalation 0.390 to 0.682 mg/L (rat) - -

http://npic.orst.edu/factsheets/archive/fiptech.html#prop

Fipronil – Acute toxicity

https://parasitipedia.net/index.php?option=com_content&view=article&id=2686&It emid=2991

(30)

Signs of Toxicity – Humans

 Ingestion :

Sweating, nausea, vomiting, headache, abdominal pain, dizziness, agitation, weakness, and tonic-clonic seizures.

 Case report :

50-year-old, after spraying with a fipronil product for 5 hrs

Symptoms were reported after 2 hours and resolved spontaneously

(31)

Signs of Toxicity - Animals

 Mice injected intraperitoneally

 tonic-clonic seizures, facial clonus, or head twitching (Mice, IP)

 Rat and mice, single dose, Oral or inhalation

 Changes in activity or gait, hunched appearance, tremors, convulsions, and seizures

 Mice, fed doses of fipronil (87.4-97.2%) in the diet for 6 weeks

 Overactivity, irritability, abnormal gait or posture, body tremors, convulsions, and death

 52-week chronic rat feeding study

 reduced feeding and food conversion efficiency, reduced body weight gain, seizures and seizure-related death, changes in thyroid hormones, increased mass of the liver and thyroid, and kidney effects.

(32)

-Central nervous system

-Most frequent symptoms : Ataxia, hyperreactivity, tremor, cramps, convulsions, abnormal gait, seizure

-Other symptoms : twitching, nodding, aggression, sweating, nausea, lack of appetite, vomiting, headache, abdominal pain, dizziness, agitation and weakness.

-Symptoms appear a few hours after exposure, but depend strongly on the formulation, the dose and the kind of contact

-Sustained skin exposure can cause local dermatitis (skin irritation) with pruritus (itching) and erythema (red skin)

-In chronic toxicity studies in rats, liver, kidneys and thyroid gland were also affected.

(33)

Fipronil

(34)

http://parasitipedia.net/index.php?option=com_content&view=article&id=2686&Itemi d=2991

http://npic.orst.edu/factsheets/archive/fiptech.html#prop

California Department of Pesticide Regulation. Environmental Fate of Fipronil.

(December 2001).

http://www.pw.ucr.edu/textfiles/fipronil.pdf [Accessed 8-8-10].

Environmental Protection Agency. Fipronil Use on Rice (Regen, Icon) and Pets (Frontline) HED Risk Assessment. (May 1998) [Accessed 8-8-10].

National Institute for Occupational Safety and

Health. Fipronil. http://www.cdc.gov/niosh/ipcsneng/neng1503.html [Accessed 8-8-10].

Pesticide Action Network North

America. Fipronil. http://www.pesticideinfo.org/Detail_Chemical.jsp?Rec_Id=PC35768 [ Accessed 8-8-10].

National Pesticide Information Center. Fipronil Technical Fact

Sheet. http://npic.orst.edu/factsheets/fiptech.pdf [Accessed 8-8-10].

http://parasitipedia.net/index.php?option=com_content&view=article&id=2686&Itemi d=2991

https://ipmworld.umn.edu/bloomquist-insecticides References