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2015 Biotoxin Illness Understanding Toxins Jyl Burgener Midwest Area Biosafety Network (MABioN) MABioN February 18, 2016 Jyl Burgener, M.S. MBA, RBP, CBSP Topics 1. Definition and Characteristics of Toxins 2. Regulations Regarding Toxins 3. Inactivation of Toxins 4. Human Health Considerations of Toxins 2 Jyl Burgener, M.S. MBA, RBP, CBSP Definition of Toxins Simple definition of toxin: a poisonous substance produced by a living thing Full definition of toxin: • a poisonous substance • a specific product of the metabolic activities of a living organism • usually very unstable • notably toxic when introduced into the tissues, and • typically capable of inducing antibody formation 3 Jyl Burgener, M.S. MBA, RBP, CBSP Political Definition North Atlantic Treaty Organization (NATO) vs Warsaw Pact Biological or chemical agent? NATO opted for biological agent, and the Warsaw Pact, like most other countries in the world, for chemical agent. According to an International Committee of the Red Cross review of the Biological Weapons Convention: "Toxins are poisonous products of organisms; unlike biological agents, they are inanimate and not capable of reproducing themselves", "Since the signing of the Convention, there have been no disputes among the parties regarding the definition of biological agents or toxins" 4 Jyl Burgener, M.S. MBA, RBP, CBSP Biotoxin The term "biotoxin" is sometimes used to explicitly confirm the biological origin. Biotoxins can be further classified into: fungal biotoxins, or short mycotoxins, microbial biotoxins, plant biotoxins, short phytotoxins and animal biotoxins. 5 Jyl Burgener, M.S. MBA, RBP, CBSP Characteristics of Toxins Extremely potent Often mixtures Directly damage host tissues Disable the immune and nervous systems 6 Jyl Burgener, M.S. MBA, RBP, CBSP Toxins are Extremely Potent Toxin LD50 Satratoxin 24 ug/Kg Ricin 0.02 ug/Kg Botulinum .0003 ug/Kg Cyanide 1000 ug/Kg Strychnine 2000 ug/Kg 7 Jyl Burgener, M.S. MBA, RBP, CBSP Toxins are Often Mixtures Some organisms make a toxin Some organisms make multiple toxins e.g. Penicillium may produce more than 100 different mycotoxins ; May vary according to specific isolate and prevailing growth conditions. Stachybotry chartarum also produces numerous compounds: Trichothecene mycotoxins implicated in health effects including macrocyclic trichothecense verrucarins B and J, riridin E. satratoxins F, G, H and isisatratoxins F, G H 8 Jyl Burgener, M.S. MBA, RBP, CBSP US Regulations Regarding Toxins Select Agents and Toxin Regulations 7 C.F.R. Part 3319 9 C.F.R. Part 12142 42 C.F.R. Part 73 9 Jyl Burgener, M.S. MBA, RBP, CBSP International Regulations: Biological and Toxin Weapons Convention (BWC) Supplements the 1925 Geneva Protocol Prohibits use of but not possession or development of chemical and biological weapon 173 countries are party to it (Dec. 2014) Prohibit development, production and stockpiling of biological and toxin weapons No formal verification method to monitor compliance limits effectiveness of the convention U.S. Congress passed the Bioweapon Anti-Terrorism Act in 1989 to implement the BWC 10 Jyl Burgener, M.S. MBA, RBP, CBSP Inactivation of Toxins – Guidance Appendix I—Guidelines for Work with Toxins of Biological Origin Prudent Practices in the Laboratory – Ch.6 Working with Chemicals – Ch. 6.D. Working with Substances of High Toxicity OSHA Lab Standard – Particularly Hazardous Substance 11 Jyl Burgener, M.S. MBA, RBP, CBSP Inactivation of Toxins: Steam Steam Heat (Autoclaving) Generally, many of the higher molecular weight, proteinacious bacterial biotoxins can be inactivated by autoclaving for 1 hour at 121°C. Autoclaving should not be used for destruction of low molecular weight biotoxins such as mycotoxins, marine and reptile venoms. 12 Jyl Burgener, M.S. MBA, RBP, CBSP Steam Autoclaving (121 oc/15 psi/1 hr) Abrin Pertussis toxin Botulinum neurotoxins Pseudomonas exotoxin A Cl. difficile – binary toxin c, Ricin enterotoxin A, Toxin A, Toxin B Shigatoxin & Shiga-like ribosomes inactivating Cl. Perfringes (epsilon) proteins Cl. Tetani (tetnus toxin) Staphylococcal enterotoxins Diptheria toxin 13 Jyl Burgener, M.S. MBA, RBP, CBSP Inactivation of Toxins: Chemical Chemical Inactivation – Sodium Hypochlorite (NaOCL) – use a 2.5% solution, equivalent to a 50% Bleach solution. Minimum of 30 min. exposure. Sodium Hydroxide (NaOH) – 1 N; Minimum of 1 hour exposure (Prions) usually hold overnight 14 Jyl Burgener, M.S. MBA, RBP, CBSP Chemical Inactivation – 2.5% NaOCL (w/v) Anthrax Lethal/Edema Ricin Toxin (PA & LF)/(PA & EF) Saxitoxin Botulinum neurotoxins Staphylococcal Brevetoxin enterotoxin Diptheria toxin Tetrodotoxin (TTX) Microcystines T-2 mycotoxin Palytoxin 15 Jyl Burgener, M.S. MBA, RBP, CBSP Chemical Inactivation – NaOH 1 N 1 hr Botulinum neurotoxin Staphylococcal Enterotoxin 16 Jyl Burgener, M.S. MBA, RBP, CBSP Inactivation of Conotoxins Depends on the presence or absence of disulfide bonds. Conotoxins with disulfide bonds will be incubated with an excess of dithiothreitol (DTT) (usually 10-20mM buffered solution, pH8.7) for at least 1 hour at room temperature or 30 minutes at 50oC. Then, an equal volume of 50-100mM solution of iodoacetamide (buffered solution, pH8.7) will be added and incubated for 1 hour at room temperature. 17 Jyl Burgener, M.S. MBA, RBP, CBSP Human Health Considerations of Mycotoxins 80% of Clinical Toxin exposure is mold/mycotoxin exposure. Affects more humans than any other toxin More detailed information is known 25% of the population has an inability to process/clear mold toxins which leads to a series of biochemical alterations in their bodies 322 mil x .25% = 80.5 mil people There are many mold symptoms, because the illness affects multiple systems in the body Not all molds are toxigenic, but Stachybotrys, Penicillium, Aspergillus, and Chaetomium are the most common toxigenic ones. 18 Jyl Burgener, M.S. MBA, RBP, CBSP Symptoms of Mycotoxin Exposure Fatigue ♦Weakness ♦Aches ♦Muscle Cramps ♦Unusual Pain ♦Ice Pick Pain ♦Headache ♦Light Sensitivity ♦Red Eyes ♦Blurred Vision ♦Tearing ♦Sinus Problems ♦Cough ♦Shortness of Breath ♦Abdominal Pain ♦Diarrhea ♦Joint Pain ♦Morning Stiffness ♦Memory Issues ♦Focus/Concentration Issues ♦Word Recollection Issues ♦Decreased Learning of New Knowledge ♦Confusion ♦Disorientation ♦Skin Sensitivity ♦Mood Swings ♦Appetite Swings ♦Sweats (especially night sweats) ♦Temperature Regulation or Dysregulation Problems ♦Excessive Thirst ♦Increased Urination ♦Static Shocks ♦Numbness ♦Tingling ♦Vertigo ♦Metallic Taste ♦Tremors The typical patient will exhibit an average of 23 symptoms 19 Jyl Burgener, M.S. MBA, RBP, CBSP Human Health Effects - Detection Mycotoxins: the direct cause of diseases (eg asthma), liver and kidney cancer, permanent genetic damage, brain damage, nervous system damage and even death Mycotoxins can be detected in urine Blood tests can be used (measure MMP9 and TGF-beta and C4a in particular) Genetic testing Visual Contrast Sensitivity Test Neuro Quant 20 Jyl Burgener, M.S. MBA, RBP, CBSP HLA Genetics Currently 12 genes associated with the clearance of toxins from the body Located on Chromosome 6 Do not allow an individual to eliminate circulating biotoxins Bioaccumulation occurs Patient develops chronic illness Genotype –HLA-DR found in ~25% of population ~ 90% of patients developing chronic Lyme disease and chronic ciguatera poisoning have HLA-DR 21 Jyl Burgener, M.S. MBA, RBP, CBSP Visual Contrast Sensitivity Ken Hudnell (neurotoxicologist) was the first to use VCS to measure the effects of biotoxin exposure and heavy metal toxicity and as a marker for neurotoxic exposures. VCS testing has also revealed neurologic deficits associated with exposure to toxic Pfiesteria sp. and other biotoxins ( Ciguatera ;Chronic Ciguatera Seafood Poisoning), cyanobacteria such as Cylindrospermopsis and Microcystis, various species of fungi such as Stachybotrys, Aspergillus, Penicillium, and Fusarium, and Brown Recluse spider venom as well as Borrelia burgdorferi (Lyme disease organism) 22 Jyl Burgener, M.S. MBA, RBP, CBSP Visual Contrast Sensitivity (VCS) Test 92% of people with biotoxin illness have a positive VCS test VCS has been a sensitive indicator of neurotoxicity induced by organic solvents. Persistent or permanent VCS deficits in the presence of normal visual acuity have been observed in styrene and mixed-solvent exposed workers in the absence of detectable optical, retinal or optic nerve head pathology. 23 Jyl Burgener, M.S. MBA, RBP, CBSP NeuroQuant Brain MRI A volumetric MRI which measures regional brain structures known to deteriorate in patients with Alzheimer’s disease and other related neurodegenerative disorders. NeuroQuant is the only volumetric MRI application to use an FDA approved database of normal same age peers for comparison. 24 Jyl Burgener, M.S. MBA, RBP, CBSP NeuroQuant Brain MRI People with elevated TGF-beta and MMP9. show in NeuroQuant studies a swelling of the frontal lobes, the hippocampus and the cerebellum and a shrinkage of the caudate. The frontal lobe is where the executive function is found. The hippocampus is associated with mood. The cerebellum is associated with movement disorders. The caudate is very dopamine rich and is highly associated with moods and feeling good. 25 Jyl Burgener, M.S. MBA, RBP, CBSP Common Mycotoxins Aspergillus: Aflatoxin B1 – Liver cancer Fusarium: Zeatralenone; Estrogen disturbance Penicillium Tremogenic mycotoxins Stachybotrys;
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