Toxicant-Induced Loss of Tolerance (TILT) theory of MCS originally described by S.

[Guest guest]

The " TILT " theory of MCS seems to be the one that is the most

respected by the MCS community. The person who first put forward the

idea is S. .

Here is an article by her on it:

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Low-Level Chemical Exposures

A Challenge for Science and Policy

Excerpted with permission from Environmental Science & Technology,

November 1, 1998, 32, 508A--509A.Copyright 1998 American Chemical

Society.

VIEWPOINT

NICHOLAS A. ASHFORD AND CLAUDIA S. MILLER

Once thought to be safe, there is mounting evidence that human

exposure to chemicals at low levels can be harmful. The exposures are

linked with adverse biological effects, including endocrine disruption

( 1 ), chemical sensitivity ( 2 ), and cancer ( 3). Prior

susceptibility of an individual, whether inborn or environmentally

induced, followed by other lifetime exposures, can cause irreversible

injury. Unfortunately, although emerging scientific knowledge

associated with these exposures indicates a need to change the way we

think about chemicals and health, new theories are slow to emerge

(see box on next page) 4 ).

SIDEBAR: Evolution of scientific knowledge

We are just now beginning to recognize the link between chemicals and

new public health problems that challenge the tenets of traditional

toxicology and medicine. These include birth defects and other damage

due to developmental toxicants, autoimmune diseases (including lupus,

scleroderma, and Sj<>gren's Syndrome), chronic conditions in children

(such as attention deficit hyperactivity disorder, depression, and

asthma) that have become more prevalent in the past few decades,

chemical sensitivity including its overlaps with sick building

syndrome, unexplained illnesses of Gulf War veterans, chronic fatigue

syndrome, fibromyalgia, toxic encephalopathy, and new links to cancer,

including childhood cancers.

Problem characterization: These emerging health problems are

characterized by common threads that provide a new perspective on

disease.

Nature: They are a departure from classic diseases such as

tuberculosis and heart disease. Communication systems or

networks--including the endocrine system, the immune system, and the

neurological system--rather than specific organs of the body, appear

to be targeted.

Cause: No single cause has been identified for each of these

conditions. Often there are no clear biomarkers for either exposure or

disease. Consequently, classical epidemiology is less able to

identify susceptible or sensitive subgroups.

Stages: Disease becomes manifest after two or more stages or events

occur. For example, some cancers may proceed first by initiation--a

mutation that alters the genetic material of the cell--followed by the

promotion of cancer cells to a recognizable tumor. These stages can

involve different chemicals, radiation, or viruses. It has been

hypothesized that Toxicant-Induced Loss of Tolerance (TILT), a new

theory of disease, leading to chemical sensitivity, also proceeds via

a two-stage process: an initial exposure to high levels of certain

chemicals (or repeated exposures at lower levels), followed by

triggering of symptoms by everyday chemical exposures at levels that

do not appear to affect most people ( 2 ) .

Time: The time between the first and subsequent stages of disease can

be long enough to obscure the connection between exposures and

ultimate disease. The latency of chemically caused cancer is measured

in years. Observable reproductive system failure can occur years after

endocrine disruption. Chemical sensitivity reportedly can develop

months after the initial exposure and remain manifest for years. The

timing of the initiating doses appears important. Loss of tolerance

does not always require a high initial dose; smaller doses,

strategically timed, might also cause pathological loss of tolerance.

Nonclassical explanation: Classical approaches and models used in both

toxicology and epidemiology, premised on single agents disrupting

individual organs, do not explain these diseases. Moreover, the

relationship between the initiating exposure and ultimate health

effects is not monotonic. This is illustrated in the recent work of

Fred vom Saal on the endocrine-disrupting effects of bisphenol A, as

discussed in Hileman's article ( 5 ) . Endocrine disruption (ED),

TILT, and some cancers appear to represent a failure in functional and

adaptive processes in important systems or networks as a result of

chemical exposures at concentrations 3 to 6 orders of magnitude lower

than those associated with classical toxic effects in normal

individuals. Moreover, individuals exposed below " safe " thresholds to

multiple xenobiotics simultaneously, as in a sick building, are

affected.

Disease processes: Endocrine disruption (ED), TILT, and some cancers

may be interrelated. ED disrupts normal development, and possibly the

immune system, which results in increased susceptibility to certain

cancers. ED might also affect the neurological system, leading to

increased susceptibility to sensitization by chemicals. TILT manifests

itself as a loss of tolerance to everyday chemical, food, and drug

exposures in affected persons, possibly leaving these individuals more

susceptible to other diseases. Just as the general category of

infectious diseases encompasses a diverse disease spectrum involving

different organisms (which affect different organs via different

specific disease mechanisms), TILT may arise from different chemical

exposures (which, like the infectious diseases, could affect different

organ systems via different specific disease mechanisms). With TILT,

key systems of the body appear to lose their ability to adapt to

low-level chemical exposures. Finally, cancer proceeds when adaptive,

homeostatic repair processes and the immune system no longer function

as they should, although the cause of this loss of protective function

is not well understood.

Framework for response: A systems-focused approach to disease is

needed to fashion policy responses. Lack of clear biomarkers and the

time lag between initiating exposures and ultimate disease make it

technically and politically difficult to develop evidence needed for

regulating many chemicals and industrial processes or to resolve

compensation issues. We must therefore consider adoption of the

Precautionary Principle (acting preventively in the face of

uncertainty), erring on the side of caution.

Applying the Precautionary Principle requires stakeholder education,

political courage, and conviction. Concern that new problems--such as

asbestos-related cancer, and the toxic effects of benzene, lead, and

persistent pesticides--are emerging generally has begun with only a

modest suggestion of evidence. When strengthened by further

information, concern grows. Often, early warnings warranted heeding:

Predictions were in the right direction, if not understated.

Unfortunately, although precautionary actions were justified, too much

time elapsed before they were implemented, and harm occurred.

Some damage has already been done by endocrine-disrupting chemicals,

but a growing recognition of the need to address problems now presents

an opportunity to act quickly. Some aspects of endocrine disruption

and other systemic damage or injury remain uncertain, and potentially

regulated industries are opposed to costly controls. Nonetheless,

rapid intervention to prevent the next generation of developmentally

compromised or chemically intolerant individuals is possible and

advisable. Uncertainty and economic concerns may appear to pose a

dilemma for environmental legislators and regulators (they may fail to

regulate a chemical that is later discovered to be harmful, or they

may, at cost to industry and consumers, regulate a chemical and later

find that the chemical is safe to use), but potentially harmful

chemicals should be regulated when scientific evidence, although

imperfect, is compelling.

A policy response consistent with a precautionary view presents

specific challenges: Policies must be harmonized and coordinated among

the major stakeholders. A new corporate stewardship is required, one

that is harmonized with the customers' and the public's expectations

that companies will adhere to the Precautionary Principle. Rather than

serving as an arbiter or mediator of conflicts among stakeholders,

government must return to its role as a trustee of the environment,

public health, and sustainability, and direct its interventions and

research support to all phases of multistage diseases, for example, to

promoters, as well as initiators of cancer. Media representatives must

accurately report the complex evolution of scientific understanding.

Public interest groups and nongovernmental organizations should

strengthen linkages among disparate groups and continue their role as

educators and advocates for precautionary protections. The

international community must commit to a program of relevant research

and to the establishment of multilateral environmental agreements,

such as the proposal to ban persistent organic pollutants. These

agreements should not result in banning endocrine-disrupting chemicals

by substituting chemicals that produce other harmful effects or that

put workers at significant risk, and the strategy for dealing with

endocrine disrupters and other harmful chemicals must ensure that less

developed nations have access to needed technologies.

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References

(1) Colborn, T.; Dumanowski, D.; Myers, J.P. Our Stolen Future ;

Dutton Press: New York, 1996.

(2) Ashford, N. A.; , C. S. Chemical Exposures: Low Levels and

High Stakes ; Wiley & Sons: New York, 1998.

(3) , D. L.; Telang, N. T.; Osborne, M. P.; Bradlow, H. L.

Environ. Health Perspect. 1997 , 101 (3), 571-576.

(4) Kuhn, T. The Structure of Scientific Revolutions , 3rd ed.;

University of Chicago Press: Chicago, IL, 1996.

(5) Hileman, B. Chem. Eng. News 1997 , 75 (12), 37-38.

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A. Ashford is a professor of technology and policy at the

Massachusetts Institute of Technology, Cambridge.

S. is an assistant professor of environmental and

occupational medicine, University of Texas Health Science Center, San

, Tex