a cause of Cl spill's/Cl worker's long term effects?/also: hormones & metabolites

[ttweed@wildrockies.org (Tony Tweedale)]

  my amateur toxicol. research often yields serendipity.  in reading about
  oxidative damage (caused by the highly charged (ie missing or extra
  electrons) therefore highly  reactive molecules, created in the chain of
  normal metabolic reduction/oxidation reactions), i learned about
  hemoprotein oxidase enzyme (MPO) that oxidises chloride (Cl-) w/ H2O2 to
  produce the unusually potent, reactive, oxidizing toxic compound
  hypochlorous acid (HOCl--which is why i's used as a bleaching agent).
  HOCl will react almost instantly w/ biological molecules, especially
  proteins, to produce lipophillic N-chloramine oxidising products (R-NHCl),
  that can penetrate cellular membrane, also react w/ proteins (such as
  enzymes or DNA or the building blocks of proteins, amino acids) and
  apparantly have even greater acute toxicity that HOCl.
  
  the catlyst enzyme MPO is apparantly quite common in the body, as are the
  reactants, chloride (a common anion used for many normal functions) and
  hydrogen peroxide (produced from normal metabolic oxidation).
  
  for the victims of the alberton, MT chlorine gas spill, and other chlorine
  exposed people such as pulp mill, chlor-alkaly, PVC production, etc.
  workers, THE SIGNIFICANCE OF THIS may  be that your ongoing (1 year and on
  in Alberton) complaints (headaches, joint aches, fatigue, loss of
  peripheral vision?, confusion, memory, etc.), which could not be explained
  by Cl2 gas because it rapidly is converted to chloride in the environment,
  MAY BE EXPLAINED by all the environmentally stable chloride in the Alberton
  environment now (the ultimate product of much of the Cl2 gas), and possibly
  in elevated chloride levels in your bodies.  lucinda, i know i told you the
  Alberton chloride was not a health concern--and it is a ubiquitous,
  biologically used ion--but i didn't consider that elevated levels of a
  useful molecule may become toxic, and i hadn't read this mechanism for
  chloride toxicity.
  
  i sent you a copy of the paper to lucinda yesterday.  see p.'s 5-9, m.
  grisham & j. mccord's 'chemistry & cytotoxicity of rective oxygen
  metabolites' (ch.1) in the book:
  
  _physiology of oxygen radicals_, ed. a. taylor et al. 1986, amer.
  physiological society, bethesda MD.
  ---
  
  btw, oxidative damage is quite commom, and the body puts up as sacrifices
  many chemicals for these reactive species to neutralize them.  oxidative
  damage results when these defences are overwhelmed.   it causes any number
  of effects, incl. aging (interestingly, probably more through a genetic
  control on aging than from random accumulated destruction caused by the
  reactions.  it is fascinating and likely no coincidence that humans have
  both the highest life span potential of any mammal and the best ratio of
  metabolic rate to oxidative protection systems).
  
  also, many mutagens (definition: chemicals that directly react with and
  damage DNA) are these unbalanced charge reactive species, therefore they
  can cause a broad range of effects, depending on what gene they damage.
  other, more direct effects include cell membrane disruption, release of
  metals (e.g Fe, Ca) from proteins, etc.
  
  inflamation, which is an immune reaction to a stress (oxidative damage,
  physical trauma, foreign particulate & chemicals (ncl. Cl2 gas), allergens,
  etc.) in turn causes damage from the immune system proteins released in
  response to the (e.g.) oxidative stress.  it is these
  proteins--neutrophils, macrophages, interleukins, tumor necrosis
  factors--cause what we recognize as inflamation (swelling, redness, edema
  (fluid accumualtion))--not the foreign stress event that initiated the
  immune resposne.  in addition to inflamation, these immune system proteins
  are associated w/ longer term effects, incl. cancer.
  
  finally (to my knowledge), hormone caused cancers, such as breast,
  prostrate & testicular, have a mechanism which involves oxidative damage.
  partial metabolism (oxidation) is a ubiquitous biological reaction.  almost
  by default (ie very comonly) many toxins AND necessary molecules are
  oxidized, often by the addition of a hydroxyl (-OH) to a carbon.  the body
  uses it as a way of activating and inactivating chemicals, incl. organic
  (carbon containing) toxins.  part of the purpose is to make toxins, e.g.,
  more water soluble and therefore excretable through the kidney into urine.
  estrogen is only active when hydroxylated [called estradiol ("-ol" =
  alcohol (eg ethanol) = a hydroxy -OH group].  when is hydroxylated at the
  16-alpha position it has different biological activity (incl the fit w/ its
  receptor molecule) than when hydroxilated at the 2 carbon position.
  similar story for the  hormone mimicking drug DES, and for PCB's--all
  activated in different ways by metabolisom.  liver cancer too, is
  promotable by certain reactive metabolic forms of a known cancer inducer,
  7,8 benzaflavone (BF), in combination with metabolized (or possibly not)
  hormones such as estradiols, DES and 2,3,7,8-TCDDioxin.  once hydroxylated,
  various hormones both induce the p450 enzymes (which help in turn partialy
  metabolize (activate) other organic toxins); and are mutagens, directly
  reacting with/damaging DNA.
  
  [these related mechanisms are in addition to the more commonly observed
  mechanism, where the hormone/receptor attaches more lightly to DNA, thus
  altering genetic expression of traits & functions].
  
  for more on hormones & oxidation see:
  
  m. metzler, g. blaich & angelika trischler (who presented at the 2nd
  citizen's dioxin confer.): 'role of metabolic activation in the
  carcinogenicuty of estrogens: studies in an animal liver tumor model', _env
  health perspectives_ 88:117-21 ('90)
  
  
  and two of the excellent mechanistic articles reprinted in cchw's current
  (nov.) _env. health monthly_ on breast cancer:
  
  devra lee davis et al: 'env. influences of breast cancer' _science &
  medicine_ 4:3:55-63 ('97)  (is also a good wide ranging discussion on the
  causes of)
  
  mary wolff & paolo toniolo: "env. o-cl exposure as a potential etiliogic
  factor in breast cancer' _env. health perspectives supplements_ 103:7:141-5
  ('95)
  
  
  Tony Tweedale (Causality is a concept not subject to empirical
  demonstration.   -David Hume)