http://www.stpcoroner.org/toxicology.html

This blog defines the different and significant types of Toxicology substances/chemical such as Norbormide, Mercury, Acrylonitrile and Hymenopteran etc. Knowing the study of adverse influence of chemicals constituents on living creatures and their environment is very important to our daily living. To avoid, limit the exposure and keep living organisms in safety mode, we study as toxicity as Toxicologists who are the groups of scientists that are taught to examine, interpret and interconnect the nature of those effects, thus providing the necessary basis for protection measures.

Systems Toxicology integrates toxic effects from human cells to population

In this blog I discussed extensively the very important parts of the substances, in order to educate, feed ,equip and update our knowledge on different facts about objects, chemicals of their use and toxicity levels to living organisms especially we humans .Then we ask ourselves;

what’s Toxicology?How do we get exposed?What  effect will it have on me  ?How do I treat this ?We should always be aware of our environments, foods, air we breath in and work places for safety protective gears.The holistic, quantitative, and mechanistic approach , allows us to determine variances of the organ molecules, cells, tissues and organisms as a whole at the exposure of these chemical it can cause DNA mutations, dysfunctional cerebrum and ultimately tumor formation.

                                    https://faculty.ucr.edu/~legneref/entomol/hymenoptera.htm            Honeybee (Apis mellifera)

Description of Hymenopterans; Small hooks, termed hamuli, seam the forewings and the smaller hindwings of these insects collectively.

Both pairs of wings work supportively during flight,

Most Hymenoptera has chewing mouthparts.

Bees are the exclusion, with modified mouthparts and a proboscis for siphoning nectar.

Hymenopteran antennae are set like an elbow or knee, and they have compound eyes.

An ovipositor on the end of the abdomen allows the female to deposit eggs in host plants or insects.Some bees and wasps use a stinger, which is actually a modified ovipositor, to protect them when susceptible.Females progress from fertilized eggs, and males develop from unfertilized eggs.Insects in this order undergo complete metamorphosis. The Hymenoptera are most significant to humans as pollinators of wild and cultivated flowering plants, as parasites of destructive insects, and as makers of honey.The Hymenoptera are remarkable for their great specialization of structure,for their varying degrees of social organization and for the highly developed condition that parasitism has reached.

The Hymenoptera are divided into two suborders:

• Symphyta -mainly sawflies and horntails
• Apocrita -wasps, ants, bees, and most parasitic forms.

Most species, however, are solitary in habit. Hymenopterans might be;

•  Parasitic or nonparasitic,
• carnivorous,
• phytophagous, or omnivorous

Habitat and Distribution-Hymenopteran insects live throughout the world, with the exception of Antartica. Like most animals; their distribution is often dependent on their food supply. For example, bees pollinate flowers and require habitats with flowering plants.

Major Families in the Order

• Apidae – honeybees and bumblebees
• Braconidae – parasitic wasps parasites of butterfly and moth larvae
• Cynipidae – gall wasps
• Formicidae – ants
• Scoliidae – scoliid wasps prey on beetle larvae
• Vespidae – hornets and yellow jackets

https://www.britannica.com/animal/hymenopteran/images-videos– For more enquiring about the life of Hymenoptera.

Mechanism of toxicity.

• The venoms of Hymenoptera are composite mixtures of enzymes and are supplied by several means. The venom device is situated in the posterior abdomen of the female.
• The terminal end of the stinger of the Apidae (honeybees) is pointed, so the stinger stays in the prey and more or less of the venom device is torn from the body of the bee, leading in its death as it flies away.
• The musculature surrounding the venom sac carries on to pact for some minutes after evisceration, instigating venom to be expelled obstinately.
• The Bombidae and Vespidae have stingers that stay functionally complete after a sting, resulting in their capacity to impose numerous stings.
• The envenomating Formicidae have secretory venom glands in the posterior abdomen and envenomate either by inserting venom via a stinger or by squirting venom from the posterior,abdomen into a bite wound produced by their mandibles.

SYMPTOMS AND SIGNS

• Most individuals will develop limited local swelling in response to a sting that is of nuisance value.
• A minority of persons will develop excessive local swelling, which could be either instant emerging and climaxing within 1-2 hours and deferred emerging hours subsequently to sting, increasing for 24-48 hours and resolving after three to ten  days . Such events only threaten life as in nearness to the airway
• Anaphylaxis is a common and life-threatening result of Hymenoptera stings and is characteristically aa a result of fast systemic release of mast cells and basophil mediators.
• Urticaria, vasodilation,
• Bronchospasm,
• Laryngospasm
• Angioedema are prominent symptoms of the reaction.
• https://www.trulynolen.ca/do-wasps-sting-us-for-no-reason/

• Anaphylactic reactions,
• Cutaneous systemic reactions, and
• Large local reactions
• An anaphylactic reaction includes signs and indications of immunoglobulin E (IgE)-mediated allergy, characteristically affecting more than one organ system. The skin urticaria and angioedema is usually involved, but respiratory or circulatory signs are also projecting. Some of the most severe reactions for instance, unexpected hypotension happen in lack of any skin findings or can be refractory to single or multiple doses of epinephrine.
• A cutaneous systemic reaction or a generalized cutaneous reaction which comprises of signs and indications limited to the skin that is, pruritus, erythema, urticaria, and angioedema, which is usually extensive and include skin that is not contiguous with the sting spot. Reactions involving angioedema of the tongue or throat, which could compromise the airway, are usually omitted from this group and considered anaphylactic reactions.
• Large local reactions  are Hymenoptera stings, that are described  as skin reactions around the spot of the sting categorized by edema, erythema and itching, with a diameter greater than 10 cm, are much more common than systemic reactions. 

Grading system for generalized hypersensitivity reactions

Hymenoptera Treatment

• As mentioned above Hymenoptera stings can result in life-threatening anaphylaxis
• The most severe reactions can be refractory to single or multiple doses of epinephrine.
• Venom immunotherapy (VIT) is highly effective and well-tolerated by most patients.
• VIT for patients with allergies to honey bee, yellow jacket, yellow hornet, white-faced hornet,
• Wasp is given using purified venoms,
• whole body extracts are used in immunotherapy for fire ant allergy.

Inconclusion, at an individual level, reasonable measures comprises minimization of situations that attract the responsible insects for instance garbage, uneaten food for yellow jackets and perfumes for honey bees and use of protective footwear and clothing. Of particular importance is the avoidance of drinking from beverage containers or straws because of the high risk of a sting in the oro-pharynx. At a community level, several of the sting allergy complications have a biological source, such as introduction of the imported fire ant into the USA where natural controls are lacking and decline of native predators (echidnas) of the jack jumper ant and intrusion of housing into the ants’ natural habitat. The rise in anaphylaxis to Ixodes bites on east coast Australia appears to coincide with success of measures to minimise introduced predators of small marsupials, natural hosts for the ticks.

References;

1. https://www.britannica.com/animal/hymenopteran
2. https://www.thoughtco.com/ants-bees-wasps-order-hymenoptera
3. https://www.uptodate.com/contents/hymenoptera-venom-immunotherapy-efficacy-indications-and-mechanism-of-action?topicRef=4095&source=see_link
4. Pucci S, D’Alò S, De Pasquale T, Illuminati I, Makri E, Incorvaia C. Risk of anaphylaxis in patients with large local reactions to hymenoptera stings: a retrospective and prospective study. Clin Mol Allergy. 2015;13:21. Published 2015 Nov 9. doi:10.1186/s12948-015-0030-z
5. https://www.worldallergy.org/education-and-programs/education/allergic-disease-resource-center/professionals/allergy-to-insect-stings-and-bites

What is Acrylonitrile? 

Acrylonitrile (acrylan, vinyl cyanide) is a, toxic, colorless to pale yellow, liquid, man-made chemical with a sharp, onion or garlic-like odor.

Acrylonitrile is used mostly to make plastics, acrylic fibers, and synthetic rubber and in the past as a pesticide.

Because acrylonitrile evaporates quickly, it is most likely to be found in the air around chemical plants where it is made.

Acrylonitrile breaks down quickly in the air. It has been found in small amounts in the water and soil near manufacturing plants and hazardous waste sites
This substance, is harmful to the eyes, skin, lungs, and nervous system, it may cause cancer.

Workers may be harmed from exposure to acrylonitrile. The level of exposure depends upon the dose, duration, and work being done.

In water, acrylonitrile usually breaks down in about two to three weeks, although this can vary depending on conditions.

For instance, high concentrations of acrylonitrile such as might occur after a spill tends to be broken down more slowly. In one case, measurable amounts of acrylonitrile were found in nearby wells one year after a spill.    Link

     Nitrile hnad Gloves      Factory workers

https://www.cdc.gov/niosh/topics/acrylonitrile/default.html/

https://www.wordnik.com/words/acrylonitrile

These are examples of workers at risk of being exposed to acrylonitrile include the following:

• Workers involved in the manufacturing of acrylic fibers and plastics
• Employees who work in the coatings and adhesive industries
• Workers in the manufacture of other chemicals like adiponitrile
• Factory workers producing nitrile rubber production.

Acrylonitrile Plant ;PLawww.asahi-kasei.eu/acrylonitrile

How Humans are Exposed to Acrylonitrile(Absorption, Distribution, Metabolism and Excretion (ADME)

Acrylonitrile can enter your body if a person breathe its vapors or eat or drink acrylonitrile-contaminated food or water.

Acrylonitrile can pass through the skin, but how much gets through is  unknown.

Inside the body, acrylonitrile is broken down into other chemicals, comprising cyanide.

Most of these breakdown products are removed from the body in the urine.

Generally, most acrylonitrile is removed from the body within 24 hours, but approximately 25% of what is taken in becomes attached to materials inside cells of the body.

Train pulling Acrylonitrile,derails and burns ,this evaporates in to air and causes hazard to living organisms(humans and animals) as inhalation takes place.    https://cen.acs.org/articles/93/web/2015/07/Train-Hauling-Acrylonitrile-Derails-Burns.html

Effect of Acrylonitrile On Human; Clinical Effects of Acute Exposure

Small children are more likely to be affected than adults. In several cases, children died following exposures that adults found only mildly irritating.

• Ocular exposures: The vapors are irritating to the eyes. Splash contact causes
  only transient disturbances without corneal injury.
• Diminished vision has been reported following long-term exposure.
• Dermal exposures: Dermal contact may result in burning, erythema, blister
  formation, swelling, itching, and drying, scaling, cracking and peeling of the
  skin.
• Prolonged skin contact with liquid acrylonitrile can result in systemic
  toxicity and the formation of large dermal vesicles after a period of several
  hours. The affected skin area may resemble a second-degree, thermal burn.
• Inhalation exposures: Inhalation will cause nose and throat irritation,
  dizziness, impaired judgment, tightness in the chest, difficulty breathing,
  nausea and headache.
• Severe intoxication might be ensued by abrupt loss of
  consciousness, seizures, pulmonary edema, respiratory arrest and death.
• Ingestion exposures: Ingestion may result in nausea, vomiting and diarrhea.
  Severe exposures may cause gastrointestinal hemorrhage.
• When poisoning cases do occur, symptoms are caused by tissue anoxia and include: dyspnea, a
  burning sensation in the throat, dizziness, impaired judgment, cyanosis,
  nausea, seizures and death.
• Link

Further insight on carcinogenicity of acrylonitrile is an important intermediate in the chemical industry which was reviewed and

and these are three conclusions that were observed;

•  Acrylonitrile has genotoxic effects in various tests in microorganisms and in mammal cells.
•  Chronic exposure to acrylonitrile causes tumors in rats.
• Results of epidemiological studies indicate that acrylonitrile may be a human carcinogen and Teratogen.

Acrylonitrile Treatment;

• The utmost predominant treatment for acrylonitrile polymer fouling is hydroquinone (HQ), which is only to some extent effective.
• The treatment for acrylonitrile poisoning comprises breathing pure oxygen and,
• In the case of severe exposure, precise antidotes, including those used to treat cyanide poisoning. Persons with serious symptoms might require to be hospitalized
• Administration of antidotes comprising the methemoglobin‐producing agent (MHbPA)
•  Sulfur‐providing agent (SPA) is the main to the success of emergency treatment and thus the early recovery of the victim.

For more  information on Safety Occupational Industry Terms

• Personal Protective Equipment (PPE) Link
• Federal OSHA Link
• Environmental Protection Agency (EPA) Link
• National Institute for Occupational Safety and Health (NIOSH) Link
• Permissible Exposure Levels (PEL) Link

In coclusion, Acrylonitrile is released in substantial quantities from factories, both in the air and in waste waters, and people living close by might be exposed to the chemical. Drinking-water and food might be polluted with acrylonitrile, but levels will be low, unless the soil or water supplies have been polluted through accidental spillage during production, storage, transport, or use. Contamination of food from packaging materials comprising free acrylonitrile is possible. Also more further studies has revealed that workers in factories using acrylonitrile to create other products run a greater risk of exposure than those in factories producing the chemical, where it is more effortlessly controlled. Exposure in the work-place is through inhalation and contamination of the skin.

References;

1. Koerselman W, van der Graaf M. Acrylonitrile: a suspected human carcinogen. Int Arch Occup Environ Health. 1984;54(4):317-324. doi:10.1007/BF00378585
2. https://www.cdc.gov/niosh/topics/acrylonitrile/default.html
3. https://www.atsdr.cdc.gov/PHS/PHS.asp?id=445&tid=78
4. https://www.kansashealthsystem.com/-/media/Files/PDF/Poisons/Kdhe20acrylonitrile.pdf
5. https://www.researchgate.net/figure/Summary-of-acrylonitrile-occupational-health-studies_tbl1_26713069https://
6. www.ecolab.com/solutions/acrylonitrile-solutions#f:@websolutions=[Acrylonitrile%20Solutions]&f:@webapplications=[Acrylates]
7. https://nj.gov/health/eoh/rtkweb/documents/fs/0024.pdf
8. http://www.inchem.org/documents/hsg/hsg/hsg001.htm

HISTORY

Mercury was originated from Egyptian tombs that date from 1500 BC. In China and Tibet, mercury use was believed to lengthen life, restore fractures, and sustain normally good health, although it is now recognized that contact to mercury vapor leads to staid adverse health effects. Mercury is an exceedingly uncommon element in Earth’s crust, having an average crustal abundance by mass of only 0.08 parts per million (ppm). Since it does not combine geo-chemically with those elements that constitute the majority of the crustal mass, mercury ores can be extremely concentrated bearing in mind the element’s great quantity is in ordinary rock.

Link https://en.wikipedia.org/wiki/

WHAT IS MERCURY?  

Mercury is a chemical element with the symbol Hg and atomic number 80. It is normally known as quicksilver and was previously called hydrargyrum. A heavy, silvery d block element, mercury is the only metallic element that is liquid at normal circumstances for temperature and pressure; the only other element that is liquid under these situations is the halogen bromide although metals such as Caesium,Gallium,and Rubidium melt just above room temperature .Mercury occurs in deposits throughout the world mostly as cinnabar-mercuric sulfide.The red pigment vermilion is gotten by crushing natural cinnabar or synthetic mercuric sulfide.

Link

Importance of Mercury

• For the extraction of gold and silver
• As a catalyst for chloralkali production
• In manometers for measuring and controlling pressure
• In thermometers for taking body temperature
• In electrical and electronic switches
• In fluorescent lamps
• As dental amalgam fiilings

In the 19^th century Mercury was used for various conditions including constipation,depression,child bearing and toothaches.

Mercury is used in Thermometer:       

•         Barometers,manometers,Sphygmomnometers
•         Float Valves,Mercury switches,Mercury relays
•        Fluorescent lamps and other devices.

The element’s toxicity have been directed to mercury thermometers and sphygmomanometers being essentially phased out in clinical environments in approval of substitutes such as alcohol or Galinstan filled glass thermometers and thermistor or Infrared based electronic instruments.Likewise, mechanical pressure gauges and electronic strain gauge sensors have replaced mercury sphygmomanometers. Mercury stays in use in scientific research solicitations and in Amalgam for dental restoration  in some settings.It is also used in fluorescent light, Electricity passed through mercury vapor in a fluorescent lamp produces short-wave ultraviolet light , which then causes the phosphor in the tube to  fluoresce making visible light .

While the sight of metal pouring from the hand is captivating, mercury is exceedingly toxic when inhaled or touched and should under no circumstances be handled with bare skin.

The dental amalgam comprises of known; Neurotoxin,which releases low level of mercury in the form of a vapor that can be inhaled and absorbed by the lungs .High Levels of mercury vapor exposure are associated with adverse effects in the brain and the kidneys.Mercury Poisoning  can result from exposure to water-soluble forms of mercury such as mercuric chloride or Methylmercury  by inhalation of mercury vapor, or by ingesting any type of mercury.

Link https://en.wikipedia.org/wiki/Mercury_poisoning

Chemical properties Of Mercury

Mercury does not respond with most acids; such as dilute sulfuric acid,even though oxidizing acids such as concentrated sulfuric acid and nitric acid or aqua regia  melt it to give sulfate ,nitrate and chloride .Like silver, mercury reacts with atmospheric hydrogen sulfide. Mercury reacts with solid sulfur flakes, which are used in mercury spill kits to absorb mercury spill kits also use activated carbon and powdered zinc. Mercury liquefies various metals such as gold and silver to form  Amalgams. Iron is an exception, and iron flasks have traditionally been used to trade mercury

 Chemistry and Toxico-kinetics ;

As with other metals, mercury exists in multiple oxidative states,as inorganic salts, and as organic complexes [F1]. The oxidative statuses comprise elemental mercury (Hg0), mercurous (Hg+1), or mercuric (Hg+2),Mercury in any form is toxic. The variance lies in how it is absorbed, how it is bio transformed to other mercury types the clinical signs and indications, and the reaction  to treatment modalities. Mercury poisoning can result from vapor inhalation, ingestion, injection, or absorption through the skin.

MECHANISM OF TOXICITY

Mercury has 3 forms: Elemental mercury, Inorganic salts, Organic compounds.

Conceivably the most deadly form of mercury is methylmercury

Mechanism of Toxicity

• Mercury ions release toxic influences by protein precipitation, enzyme inhibition, and general corrosive action.
• Mercury not only binds to sulfhydryl groups but also to phosphoryl, carboxyl, amide, and amine groups.
• Proteins comprising enzymes with such groups willingly accessible are vulnerable to response with mercury.
• Once bound to mercury, most proteins are condensed to inactive.
• Toxicity is in part associated to the oxidative state and to the chemical type (organic versus inorganic).
• When ingested they will be more rapidly absorbed and produce greater toxicity.
• Only about 10% of an inorganic salt whether it is of the oxidative state is still absorbed compared to 90% absorption via the GI track of the organic forms.
• This means the inorganic forms are available within the GI track to exert corrosive effects on the gastrointestinal mucosa.

Mercury poisoning  

Is a kind of metal poisoning  due to exposure to mercury

Signs depending on the type;dose, method, and duration of exposure. 

• They might comprise muscle weakness poor coordination,
•  Numbeness in the hands and feet ,
• skin rashes, anxiety, memory problems,
• trouble speaking, trouble hearing, or trouble seeing.

High-level exposure to Methylmercury is known as Minamata disease .

Methylmercury exposure in children may result in Acrodynia pink disease in which the skin becomes pink and peels.

Long-standing problems might include kidney problems and decreased intellect. The effects of longstanding low-dose exposure to Methylmercury are uncertain.

Link https://en.wikipedia.org/wiki/Methylmercury

Acrodynia   pink disease

Minamata disease

Methylmercury-most deadly.

The leading route of exposure to methylmercury is through the ingestion of fish.Most fish, both freshwater and saltwater, have methylmercury. While the GI tract is the main route of absorption, methylmercury can be absorbed through the skin and the lungs as well.Once absorbed into the circulation, methylmercury enters erythrocytes where more than 90% will be found bound to hemoglobin.Smaller quantities will be bound to plasma proteins.About 10% of the burden of methylmercury is found in the brain where it slowly go through demethylation to an inorganic mercuric form. Methylmercury willingly crosses the placenta to the fetus, where deposition within the developing fetal brain can occur.In the brain, methylmercury causes focal necrosis of neurons and destruction of glial cells and is toxic to the cerebral and cerebellar cortex.

Organic mercury can be found in three forms: aryl, small and lengthy chain alkyl compounds.The organic mercury compounds are of great interest today since, they are frequently seen in the food chain and have been used to prevent bacterial growth in medications.Organic mercury is also found in fungicides and industrial run-off.A Organic mercurials are absorbed more entirely from the GI tractthan inorganic salts in part because they are more lipid-soluble and because they bind to sulfhydryl groups.

Inorganic mercury salts are found in two oxidation states: Mercurous and Mercuric.

Mercuric chloride eroding sublimate was used as an antiseptic and although no more in  used for this purpose.it is still used for many other claims including wood preservative, photographic intensifier, dry battery depolarizer,tanning agent for leather, catalyst in the manufacture of chemicals such as vinyl chloride and disinfectants, separating lead from gold, and others.Common routes of exposure include the GI tract ensuing oral ingestion and the skin. Studies using volunteers have shown that about 7% to 15% of an ingested dose of mercuric chloride is absorbed from the GI tract.Absorption is, in part, associated to the water solubility of this compound.

Elemental mercury (Hg0) is found as a liquid with a vapor pressure of 0.00185 mm at 25°C. This means that elemental mercury is extremely volatile. For example, if a dish of mercury is placed in the center of a room where the temperature is 25°C, one could expect to measure 20 mg of mercury or( 2.4 ppm) in the air up to the distance of a radial meter surrounding the mercury.

Adults with advanced mercury poisoning may have: SYMPTOMS

• hearing and speech difficulties
• lack of coordination
• muscle weakness
• nerve loss in hands and face
• trouble walking
• vision changes       
•   Mercury poisoning indications in children and infants
• cognition
• fine motor skills
• speech and language development
• visual-spatial awareness

Treatment

• Choice of treatment depends upon the type of mercury involved, For instance, eradication of the cause of exposure may be adequate ensuing exposure to a relatively low dose of mercury vapor. As with any toxin, it is serious to get as much information as conceivable concerning the cause, time, type, and mode of mercury exposure.
• Supportive care starts with the ABCs airway, breathe, circulation, particularly when handling the inhalation of elemental mercury and the ingestion of caustic inorganic mercury, both of which may cause the onset of airway obstruction and failure.
• If the patient was exposed to mercury via the skin, decontamination might include copious irrigation of the unprotected area. Aggressive hydration might be necessary for acute inorganic mercury ingestion because of its caustic properties, and for the same reason, one should not induce vomiting.
• Gastric lavage is suggested for organic ingestion, particularly if the compound is perceived on the abdominal radiographs.
• Gastric lavage with protein-containing solutions e.g., milk, egg whites, salt-poor albumin or 5% sodium formaldehyde sulfoxylate solution could bind gastric mercury and limit its absorption.
• Stimulated charcoal is showed for GI decontamination since it binds inorganic and organic mercury compounds to some degree.
• Thiol-containing chelating agents such as dimercaprol (BAL), 2,3-dimercaptosuccinic acid (DMSA, succimer), 2,3- dimercapto-1-propane sulfonic acid (DMPS), sodium 4,5-dihydroxybenzene1,3-disulfonate (Tiron), and penicillamine which compete with endogenous sulfhydryl groups have been used for treating mercury poisoning.
• In overall, chelation treatment is more active for elemental mercury than for methylmercury eradication.
• Novel agents such as DMSA and DMPS that can be administered by mouth y are substituting the agents such as BAL that are administered by deep intramuscular injection.

In conclusion, Mercury and its compounds are toxic and ought to be handled with care, mercury is treated by most international bodies as a threat and toxic compound. The organ mercury compounds and Mercury crosses the blood brain barrier to trigger nervous breakdown, tremors and suicidal tendency. Its use for therapeutic, electrical and cosmetic purpose has been banned in some countries around in the wold. Mercury poison can be treated with Chelating therapy, and soil and sediments can be decontaminated by phyto-remediation.

References;  

https://www.niehs.nih.gov/health/topics/agents/mercury/

1. Bose-O’Reilly S, McCarty KM, Steckling N, Lettmeier B. Mercury exposure and children’s health. Curr Probl Pediatr Adolesc Health Care. 2010;40(8):186‐215. doi:10.1016/j.cppeds.2010.07.002
2. Bernhoft RA. Mercury toxicity and treatment: a review of the literature. J Environ Public Health. 2012;2012:460508. doi:10.1155/2012/460508
3. Kosnett MJ. The role of chelation in the treatment of arsenic and mercury poisoning. J Med Toxicol. 2013;9(4):347‐354. doi:10.1007/s13181-013-0344-5
4. Kazantzis G. Mercury exposure and early effects: an overview. Med Lav. 2002;93(3):139‐147.
5. Mercury Toxicity and Treatment: A Review of the LiteratureJournal of Environmental and Public Health
6.  journal-article DOI: 1155/2012/460508
7. Hong, YS; Kim, YM; Lee, KE (November 2012). Methyl exposure and health effects. Journal of Preventive Medicine and Public Health = Yebang Uihakhoe Chi. 45 (6): 353–63. doi:10.391/jpmph.2012.45.353.PMC 351445.PMID 2330465
8. Liang YX, Sun RK, Chen ZQ, Li LH (1993). “Psychological effects of low exposure to mercury vapor: Application of computer-administered neurobehavioral evaluation system”. Environmental Research. 60 (2): 320–327. Bibcode:1993ER…..60..320L.

CHEMICAL  STRUCTURE

The figure shows Norbormide as a New Probe for Living Cell Imaging ; Chemical structures of (A) Norbormide and (B) its fluorescent derivative NRB-AF12. (C) Live cell imaging of LX2 hepatic stellate cells fluorescently labeled with 500 ηM NRB-AF12 for 30 min. Magnification 40x; scale bar 20 μm. (D) LX2 cells stained with NRB-AF12 were fixed and imaged by confocal microscopy. Magnification 60x; scale bar 20 μm.

INTRODUCTION

Norbormide (Raticate, Shoxin) is a toxic composite used as a rodenticide or an acute acting selective rat toxicant. It has numerous mechanisms of action, acting as a vaso-constrictor  and calcium  channel blocker, but is selectively toxic to rats and has relatively low toxicity to other species, due to a species specific action of opening the permeability transition pores in rat . mitochondria .It was discovered during routine screening of a diversity of agents for pharmacological activity at McNeil Laboratories, Fort Washington, Pennsylvania, USA. Norbormide was synthesized in the exploration for a novel anti-rheumatic drug. It was deliberated as a uncertain value for that movtive and  was  further  studied  as  an  appetite  suppressant originally  in house mice(Mus musculus)and  cats(Felis catus),  with  no  toxic  effects ,and  then  in  rats. The alterations in impressionable were so striking, it was at first assumed that a mistake had been produced. Nevertheless, the  uttermost  vulnerability  of  rats was  established  when  the  experiments  were  reiterated. It  was further  studied again and presented to representatives attending the 149th National  Meeting  of  the  Chemistry  Society  in  Detroit, Michigan  in  1965 as  a  infrequent  species-specific  rodenticide and marketed as Raticate and Shoxin. Its use reduced in the 1970s as anticoagulant toxins became more prevalent. Taste loathing had restricted its efficiency, and field efficacy outcomes were commonly sub-standard .

  Anticoagulant rodenticides have been the foremost development for the control of rodents worldwide for both crop protection and conservation . The slow onset of action ensuing ingestion of anticoagulant baits helps confirm that even wary rodents will ingest sufficient toxic bait to cause death. Hence, it is not surprising that after the introduction of warfarin and the other anticoagulants, the importance of the non-anticoagulants was reduced, at least for commensal rodent control . This applied to Norbormide as well as the older poisons such as strychnine and arsenic, notwithstanding the remarkable species   specificity   of   Norbormide.

Rat poison vendor’s stall at a market in Linxia City , China

 Norbormide provokes vasoconstriction  (narrowing)  of small arteries and vasodilation (widening) of large arteries in  rats ,  which  induces a  rapid  fall  in blood  pressure.  Death possibly results from circulatory disorders and heart failure . As  it  is  acute-acting  it  is  likely  to  be  more humane  than  most  other  rodenticides,  because  of  the somewhat short time to death and duration of symptoms of poisoning when associated with anticoagulant rodenticides and cholecalciferol. As noted above, norbormide is highly toxic to members of the genus Rattus compared with other mammals or birds . Rats are 150-fold and 40-fold more sensitive to norbormide than house mice and guinea pigs (Cavia porcellus) respectively, while most other mammals and birds tested are >200-fold less sensitive . Two  New  Zealand  research  teams, one  presently sponsored by the Department of Conservation Predator Free 2050  fund assisting Land care  Research  with  Orillion (formerly ACP Ltd),and the second generation through investment by Invasive Pest Control Ltd. ,are looking at different ways of  improving  the effectiveness  of  norbormide  and creating  it  in  forms  which  are  more  pleasant . If  either  or both groups  are effective,  it  will  be  a  huge  advance  for  targeted  pest control with no non-target influence.

Derivative and Mechanism of Action

Research have been done in which was studied for derivative compounds of Norbormide that are more toxic. Addition or substitution of various groups never turned out to give considerably more toxic compounds. In most cases compounds were acquired, being considerably less toxic. An issue of using Norbormide as a rodenticide is bait shyness; this signifies that after the rat consumes a small bit of it, the rat becomes ailing and evades the toxin at that time; likewise the savor is presumed to be awful. Currently, researcher has been seeking for prodrugs of Norbormide that delivers the toxicant slowly and thus detain the toxic impacts. Pro-drugs have been found that seem to have these properties. Following researches need to be done for improvement before usage ultimately could be possible.

The mechanism for the vasoconstrictor effect is expected to be arbitrated by the modulation of calcium influx. This influx of calcium can leads to contraction in the myocytes. Perhaps the influx of calcium is interceded by the phospholipase C (PLC)-coupled receptors, in rat peripheral artery myocytes. Further all study has revealed that in respiratory, urinary and gastrointestinal smooth muscle there was not any contraction by Norbormide.

The signs of Norbormide were very alike to the improved known Ca2+ entry blocker agents. Consequently, norbormide is not solely species specific but as well as tissue specific. Norbormide has a strong influence on the mitochondria in the cell. So, Norbormide transmit through the outer mitochondrial membrane (OMM) to the inner mitochondrial space. At this location or at the matrix it persuades the permeability transition pore (PTP). This PTP is an inner mitochondrial membrane (IMM) channel, whose opening leads to an increasing permeability for ions with an exclusion size of about 1500 Da.The convey of Norborimide derives from a Translocation protein (TSPO) also identified as peripheral benzodiazepine receptor. The Translocation protein (TSPO) is selective for the norbormide transport in rats. There are a few discrepancies in amino acids, but the position of 113 is very similar in between the species and other species like dogs, humans and chickens. Where the rat have at position 113 a methionine (M) others species have a leucine amino acid, this outcome, possibly for the diverse magnitude of transport among rat and other species.

Signaling Mechanisms for the Selective Vasoconstrictor Effect of Norbormide on the Rat Small Arteries

BIO-TRANSFORMATION

In vitro experiment

In vitro studies on liver preparations from rats and other rodents discovered that hydroxylation is the main procedure throughout the metabolism of Norbormide. Moreover, the metabolites amid the sexes of the rat appeared to diverge from one another. First and foremost when Norbormide had been incubated with the liver S9 fraction, a few metabolic products were observed. The S9 fraction has been defined as “Supernatant fraction acquired from an organ (usually liver) homogenate by centrifuging at 9000 g for 20 minutes in an appropriate standard; this fraction comprises cytosol and microsomes.” The S9 fraction consists of two constituent:

The microsomes constituent which incorporate cytochrome P450 isoforms (phase I metabolism) and

The cytosolic component which contains transferases  (phase II metabolism).

A combination of four active endo-isomers of NRB (U, V, W and Y) made four major metabolites in rat liver S9 and cytosolic arrangements after incubation. The isomers are distinctly not pure compounds, but research with pure V isomer and a mixture of U and V isomers pointed out that each isomer undergoes metabolism to be formed into a single product in rat. Mass spectrometry confirmed that all metabolites had a mass consistent with a hydroxylated metabolite of NRB. Because female rats are more sensitive to Norbormide than the male species, the level of metabolites are higher in females than in males. The same metabolites were found in guinea pigs, even though the levels of metabolism in these rodents are considerately lower equated to those in rats.

In mice two metabolites were perceived:

One metabolite of the V isomer (V1) which was also found in the rat preparations and,

Another, new metabolite of the V isomer (V2).

In vivo experiment

After getting blood from rats 10 and 30 minutes after oral administration, plasma and red blood cell fractions were evaluated in search for either parent compounds or hydroxylated metabolites. Though, neither was found, which either means that the absorption did not take place or the compounds underwent a quick clearance from the body. Whole blood samples certainly displayed traces of the parent compound and a metabolite (M3) with molecular mass of 226, in samples from both female and male rats. The level, in which this metabolite ensued, seemed to be once again higher in the female rats than in the male species. M3 was not found in any other rat or mouse tissue. This suggests that M3 may be formed by gut microflora in rats. After Norbormide had orally been given, an assessment of both rat and mouse liver discovered traces of the parent compound. Associating the metabolite levels in sexes and species, a meaningfully higher amount was discovered in the female rats than in the male rats or the mice. High Performance Liquid Chromatography (HPLC) chromatograms liver arrangements from female of and male rats show the detection of four metabolites (U1, V1, M1, M2).

TOXICKINETICS

The distinctive toxicity of Norbormide has been determined by performing animal experiments by using various species of rodents. The toxic dose was orally administered. Rats, particularly the female species, experience even after given the small amount of Norbormide the effects of the toxin. Norbormide is toxic to guinea pigs and mouse either, but to a lesser degree. There is no consistent evidence accessible about LD50 standards in humans. Even though, Norbormide is a rodenticide, and specifically toxic for brown rats, human beings could be visible to Norbormide through inhalation and dermal contact.

Exposure Acute toxic level Oral LD50 (mg/kg)

• Rat (male) 15
• Rat (female) 5
• Guinea pig 620
• Mouse 2250

Norbormide Organs Target

Norbormide is precisely toxic to rats, but it’s moderately harmless to other rodents and mammals. In all animals tried and also in the rat aorta and extravascular smooth muscle tissue, Norbormide displays vasorelaxant properties in the arteries. Additional effect of Norbormide is stimulation of corticosterone and aldosterone release in both rat and mice adrenal gland by enhancing late phase of steroid-hormone synthesis.

Signs and symptoms of toxicity

The influences of norbormide are caused by the endo-isomers, but the exo-isomers R, T and X showed no contractile effects on the rat arterio smooth muscle. There was only a relaxing result on the muscle. In animal studies of Rozkowksi, he indicated that the impacts that are triggered by Norbormide are irretrievable .Additional study has revealed that there were respiratory depressions after the cardiovascular effects in the rats which were treated with norbormide in vivo. Symptoms in rats are mild and short-lived compared with other rodenticides. Norbormide has no chronic toxic effects on non-target species. For example, following treatment for up to 60 days, dogs tolerated a dose equivalent of 1000 ppm without ill effect. At 10,000 ppm they lost appetite and looked ill . Pharmacokinetic studies indicate Norbormide is readily metabolized and unlikely to be persistent (Ravindran et al. 2009a, 2009b) and secondary poisoning studies conducted by Russell (1965) showed no ill effects in cats, dogs, and pigs. Humans given large doses exhibited a slight decrease in blood pressure which normalized after two hour.

However, there’s no evidence for  Carcinogenicity finding in Norbormide .

 Norbormide Treatment

Reports of human volunteers ingesting up to 300 mg/kg displayed no clinical outcome, other than small reductions in both temperature and systolic blood pressure. Because this agent is basically nontoxic, no specific treatment is needed after ingestion. Parents are usually advised to watch the child in the home for four hours. All suicidal ingestions warrant prompt assessment for psychiatric intervention

Link to article on Specific toxicity in six rodent species from China of a new modified norbormide  ,

credit to; Xi Ma, Brian Hopkins, Xincheng Gao, Zhiyong Feng & Deng Wang (2019) Specific toxicity in six rodent species from China of a new modified norbormide, New Zealand Journal of Zoology, 46:4, 275-284, DOI: 10.1080/03014223.2018.1540996

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